Cyclic alkynes and derivatives thereof

Abstract

Disclosed herein are compounds that can be used in a click reaction. These compounds are easy to store and handle as they are stable in air in various pHs. The compounds disclosed herein are also highly soluble.

Description

CYCLIC ALKYNES AND DERIVATIVES THEREOF REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 697398, filed September 20, 2024, the disclosure of which is hereby incorporated by reference in its entirety herein. BACKGROUND Field

[0002] Embodiments provided herein relate to the compounds that can be used in a click reaction. Specifically, embodiments herein relate to cyclic alkynes and derivatives thereof. Description of the Related Art

[0003] A click reaction is a specific type of "click chemistry" that follows strict criteria, including high yields, simple conditions, readily available starting materials, and the formation of only harmless byproducts, leading to efficient and reliable molecule creation. The most common example is the Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC), which joins an azide and a strained alkyne to form a stable 1,2,3-triazole ring. Click reactions are widely used in drug discovery, materials science, and bioconjugation because they can be performed under mild, often aqueous conditions, and even in living systems, a property known as bioorthogonality.

[0004] Strained cyclic alkynes are valuable tools in bioorthogonal chemistry because of their high reactivity, but existing scaffolds may show limited stability under air, pH extremes, or reactive conditions. In addition, certain reported ring systems restrict further functionalization, reducing their versatility. Developing new heterocyclic alkynes with enhanced stability and tunable properties provides a promising platform for applications in drug discovery, chemical biology, and diagnostics. SUMMARY

[0005] Disclosed herein include a compound having the following structure:X1X2O N Y I); wherein X1, X2, X3, X4, X5, and X6tly H, alkyl, aryl, or halogen; or X3and X4 or X5 and X4 together form a saturated or unsaturated 3- to 9- membered carbocyclic ring or heterocyclic ring having one or more heteroatoms selected from N, O, or S, wherein the carbocyclic ring and heterocyclic ring is substituted by halogen; Y is L1-L2-L3-Z; L1is absent l d f h i i f and or; R2is H or alkyl; R’ is H, alkyl, –(CH2)b–phosphorylcholine; –(CH2)b–COOR2,r –(CH2)b–C(O)NH2, wherein b is 1, 2, or 3; z is 1, 2, 3, or 4; m is an integer between 1 and 15; n is 0, 1, 2, or 3; and is aryl or heteroaryl.

[0006] L2is absent or selected from the group consisting o ,, of nd; wherein M is optionally substituted C1-C5 alkylene, optionallysubstituted C2-C4 heteroalkylene, arylene, heteroarylene, or C5 or C6 cycloalkylene; R3 is H or alkyl; R5is H, alkyl, or; R4is alkyl, optionally substituted aryl, or heteroaryl.

[0007] Z is selected from the group consisting of H, OH, halogen,; wherein R6 is selected from the group consisting of N-hydroxysuccinimide (NHS), sulfo-NHS, pentafluorophenyl (PFP), 4-nitrophenyl (PNP), hydroxybenzotriazole (HOBt), HOAt, and imidazolide esters; X is halogen; and a is 0 or 1. DETAILED DESCRIPTION

[0008] Disclosed herein are compounds include novel cyclic alkynes such as Oxo, Aza-CycloNonyne (OACN) that can be used in a click reaction. These compounds are easy to store and handle as they are stable in air in various pHs, for example, at pH from 0 to 14. In some embodiemnts, the compounds are stable at a pH of 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.510, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or 14, or a value within a range defined by any two of the aforementioned values. In some embodiments, the compound’s oxalic acid / pTSA salt can be stored without the need for an inert gas (e.g., argon), light shielding or keeping at a low temperature (such as lower than room temperature). The compounds disclosed herein also exhibit stability from reductive amination, triphosgene, and mild oxidation. The compounds disclosed herein can click onto an azide group in about 12 hours at 37 °C or about 24 hours at ambient temperature. In some embodiments, the compounds disclosed herein have high solubility compared to BCN (bicyclo[6.1.0]nonyne), DBCO(dibenzocyclooctyne) or DACN (diazacyclononyne) containing compounds. In some embodiments, OACN can be prepared in ~ 50-100 g scale. Definitions

[0009] For the purpose of the present disclosure the following terminology will be used in accordance with the definitions set forth below.

[0010] "Linker" refers to a chemical moiety that links two groups together. The linker can be cleavable or non-cleavable. Cleavable linkers can be hydrolyzable, enzymatically cleavable, pH sensitive, photolabile, or disulfide linkers, among others. Other linkers include homobifunctional and heterobifunctional linkers. A "linking group" is a functional group capable of forming a covalent linkage consisting of one or more bonds to a bioactive agent.

[0011] "Hydrolyzable linker" refers to a chemical linkage or bond, such as a covalent bond, that undergoes hydrolysis under physiological conditions. The tendency of a bond to hydrolyze may depend not only on the general type of linkage connecting two central atoms between which the bond is severed, but also on the substituents attached to these central atoms. Non-limiting examples of hydrolytically susceptible linkages include esters of carboxylic acids, phosphate esters, acetals, ketals, acyloxyalkyl ether, imines, orthoesters, and some amide linkages.

[0012] "Enzymatically cleavable linker" refers to a linkage that is subject to degradation by one or more enzymes. Some hydrolytically susceptible linkages may also be enzymatically degradable. For example esterases may act on esters of carboxylic acid or phosphate esters, and proteases may act on peptide bonds and some amide linkages.

[0013] "pH sensitive linker" refers to a linkage that is stable at one pH and subject to degradation at another pH. For example, the pH sensitive linker can be stable at neutral or basic conditions, but labile at mildly acidic conditions.

[0014] "Photolabile linker" refers to a linkage, such as a covalent bond, that cleaves upon exposure to light. The photolabile linker includes an aromatic moiety in order to absorb the incoming light, which then triggers a rearrangement of the bonds in order to cleave the two groups linked by the photolabile linker.

[0015] "Functional group" is defined to include a bioactive agent or a diagnostic agent. A "bioactive agent" is defined to include any agent, drug, compound, or mixture thereofthat targets a specific biological location (targeting agent) and / or provides some local or systemic physiological or pharmacologic effect that can be demonstrated in vivo or in vitro.

[0016] Non-limiting examples include drugs, vaccines, antibodies, antibody fragments, vitamins and cofactors, polysaccharides, carbohydrates, steroids, lipids, fats, proteins, peptides, polypeptides, nucleotides, oligonucleotides, polynucleotides, and nucleic acids (e.g., mRNA, tRNA, snRNA, RNAi, DNA, cDNA, antisense constructs, ribozymes, etc).

[0017] A "diagnostic agent" is defined to include any agent that enables the detection or imaging of a tissue or disease. Examples of diagnostic agents include, but are not limited to, radiolabels, fluorophores and dyes.

[0018] "Contacting" refers to the process of bringing into contact at least two distinct species such that they can react. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0019] "Molecular weight" in the context of the polymer can be expressed as either a number average molecular weight or a weight average molecular weight. Unless otherwise indicated, all references to molecular weight herein refer to the weight average molecular weight. Both molecular weight determinations, number average and weight average, can be measured using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values can also be used, such as the use of end- group analysis or the measurement of colligative properties (e.g., freezing-point depression, boiling-point elevation, or osmotic pressure) to determine number average molecular weight, or the use of light scattering techniques, ultracentrifugation or viscometry to determine weight average molecular weight. The polymeric reagents of the present disclosure are typically polydisperse (i.e., number average molecular weight and weight average molecular weight of the polymers are not equal), possessing low polydispersity values of preferably less than about 2, as judged by gel permeation chromatography.

[0020] The phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.

[0021] "About" as used herein means variation one might see in measurements taken among different instruments, samples, and sample preparations.

[0022] "Protected,", "protected form'', "protecting group" and "protective group" refer to the presence of a group (i.e., the protecting group) that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. Protecting group will vary depending upon the type of chemically reactive group being protected as well as the reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule, if any. The skilled artisan will recognize protecting groups known in the art, such as those found in the treatise by Greene et al., "Protective Groups In Organic Synthesis," 3rd Edition, John Wiley and Sons, Inc., New York, 1999.

[0023] "Spacer," and "spacer group" are used interchangeably herein to refer to an atom or a collection of atoms optionally used to link interconnecting moieties such as a terminus of a water-soluble polymer and a reactive group of a functional agent and a reactive group. A spacer may be hydrolytically stable or may include a hydrolytically susceptible or enzymatically degradable linkage.

[0024] "Alkyl" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. For example, C1-C6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Other alkyl groups include, but are not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl can include any number of carbons, such as 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 and 5-6. The alkyl group is typically monovalent, but can be divalent, such as when the alkyl group links two moieties together.

[0025] The term "lower" referred to above and hereinafter in connection with organic radicals or compounds respectively defines a compound or radical which can be branched or unbranched with up to and including 7, preferably up to and including 4 and (as unbranched) one or two carbon atoms.

[0026] "Alkylene" refers to an alkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene. For instance, a straight chain alkylene can be the bivalent radical of -(CH2)n, where n is 1, 2, 3, 4, 5 or 6. Alkylene groupsinclude, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0027] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', - CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH- C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -CN and -NO2in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R', R" and R"' each independently refer to hydrogen, unsubstituted (C1- C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7- membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as haloalkyl (e.g., -CF3and -CH2CF3) and acyl (e.g., - C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). Preferably, the substituted alkyl and heteroalkyl groups have from 1 to 4 substituents, more preferably 1, 2 or 3 substituents. Exceptions are those perhalo alkyl groups (e.g., pentafluoroethyl and the like) which are also preferred and contemplated by the present disclosure.

[0028] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, - SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R", -NR"C(O)R', -NR'- C(O)NR"R"', -NR"C(0)2R', -NR-C(NR'R"R"')=NR"'', -NR-C(NR'R")=NR"', -S(O)R', - S(O)2R', -S(O)2NR'R", -NRSO2R', -CN and -NO2 in a number ranging from zero to (2m'+ 1), where m' is the total number of carbon atoms in such radical. R', R", R'" and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound ofthe present disclosure includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R"' and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0029] "Alkoxy" refers to alkyl group having an oxygen atom that either connects the alkoxy group to the point of attachment or is linked to two carbons of the alkoxy group. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described within. For example, the alkoxy groups can be substituted with halogens to form a "halo-alkoxy'' group.

[0030] "Carboxyalkyl" means an alkyl group (as defined herein) substituted with a carboxy group. The term "carboxycycloalkyl" means a cycloalkyl group (as defined herein) substituted with a carboxy group. The term alkoxyalkyl means an alkyl group (as defined herein) substituted with an alkoxy group. The term "carboxy'' employed herein refers to carboxylic acids and their esters.

[0031] "Haloalkyl" refers to alkyl as defined above where some or all of the hydrogen atoms are substituted with halogen atoms. Halogen (halo) preferably represents chloro or fluoro, but may also be bromo or iodo. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 1,2,3,4,5-pentafluoro-phenyl, etc. The term "perfluoro" defines a compound or radical which has all available hydrogens that are replaced with fluorine. For example, perfluorophenyl refers to 1,2,3,4,5-pentafluorophenyl, perfluoromethyl refers to 1,1,1-trifluoromethyl, and perfluoromethoxy refers to 1,1,1-trifluoromethoxy.

[0032] "Fluoro-substituted alkyl" refers to an alkyl group where one, some, or all hydrogen atoms have been replaced by fluorine.

[0033] "Cycloalkyl" refers to a cyclic hydrocarbon group that contains from about 3 to 12, from 3 to 10, or from 3 to 7 endocyclic carbon atoms. Cycloalkyl groups include fused, bridged and spiro ring structures.

[0034] "Cyclic alkyl ether" refers to a 4 or 5 member cyclic alkyl group having 3 or 4 endocyclic carbon atoms and 1 endocyclic oxygen or sulfur atom (e.g., oxetane, thietane, tetrahydrofuran, tetrahydrothiophene); or a 6 to 7 member cyclic alkyl group having 1 or 2 endocyclic oxygen or sulfur atoms (e.g., tetrahydropyran, 1,3-dioxane, 1,4-dioxane, tetrahydrothiopyran, 1,3-dithiane, 1,4-dithiane, 1,4-oxathiane).

[0035] "Alkenyl" refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1- pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can also have from 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbons. The alkenyl group is typically monovalent, but can be divalent, such as when the alkenyl group links two moieties together.

[0036] "Alkenylene" refers to an alkenyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkenylene can be linked to the same atom or different atoms of the alkenylene. Alkenylene groups include, but are not limited to, ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, sec-butenylene, pentenylene and hexenylene.

[0037] "Alkynyl" refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one triple bond. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5- hexatriynyl. Alkynyl groups can also have from 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6 and 5 to 6 carbons. The alkynyl group is typically monovalent, but can be divalent, such as when the alkynyl group links two moieties together.

[0038] "Alkynylene" refers to an alkynyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to thealkynylene can be linked to the same atom or different atoms of the alkynylene. Alkynylene groups include, but are not limited to, ethynylene, propynylene, butynylene, sec-butynylene, pentynylene and hexynylene.

[0039] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Monocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic and polycyclic rings include, for example, norbornane, decahydronaphthalene and adamantane. For example, C3-8cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbomane.

[0040] "Cycloalkylene" refers to a cycloalkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene.

[0041] "Heterocycloalkyl" refers to a ring system having from 3 ring members to about 20 ring members and from 1 to about 5 heteroatoms such as N, 0 and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and l,4-dioxa-8-aza-spiro[ 4.5]dec-8-yl.

[0042] "Heterocycloalkylene" refers to a heterocyclalkyl group, as defined above, linking at least two other groups. The two moieties linked to the heterocycloalkylene can be linked to the same atom or different atoms of the heterocycloalkylene.

[0043] "Aryl" refers to a monocyclic or fused bicyclic, tricyclic or greater, aromatic ring assembly containing 6 to 16 ring carbon atoms. For example, aryl may be phenyl, benzyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group. Aryl groups can be mono-, di- or tri-substituted by one, two or three radicals selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy and oxy-C2-C3-alkylene; all of which are optionally further substituted, for instance as hereinbefore defined; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl. Alkylenedioxyis a divalent substitute attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy. Oxy-C2-C3-alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene. An example for oxy- C2-C3- alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.

[0044] Preferred as aryl is naphthyl, phenyl or phenyl mono- or disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, especially phenyl or phenyl-mono- or disubstituted by alkoxy, halogen or trifluoromethyl, and in particular phenyl.

[0045] Examples of substituted phenyl groups as R are, e.g.4-chlorophen-1-yl, 3,4- dichlorophen-1-yl, 4-methoxyphen-1-yl, 4-methylphen-1-yl, 4-aminomethylphen-1-yl, 4- methoxyethylaminomethylphen-1-yl, 4-hydroxyethylaminomethylphen-1-yl, 4-hydroxyethyl- (methyl)-aminomethylphen-1-yl, 3-arninomethylphen-1-yl, 4-N-acetylaminomethylphen-1- yl, 4-arninophen-1-yl, 3-arninophen-1-yl, 2-aminophen-1-yl, 4-phenyl-phen-1-yl, 4- (imidazol-1-yl)-phen-yl, 4-(imidazol-1-ylmethyl)-phen-1-yl, 4-(morpholin-1-yl)-phen-1-yl, 4- (morpholin-1-ylrnethyl)-phen-1-yl, 4-(2-methoxyethylaminomethyl)-phen-1-yl and 4- (pyrrolidin-1-ylmethyl)-phen-1-yl, 4-(thiophenyl)-phen-1-yl, 4-(3-thiophenyl)-phen-1-yl, 4- (4-methylpiperazin-l-yl)-phen-1-yl, and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl optionally substituted in the heterocyclic ring.

[0046] Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R'', -NR"C(O)R', -NR"C(O)2R', ,-NR'-C(O)NR"R'", -NH-C(NH2)=NH, - NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R"' are independently selected from hydrogen, (C1-C4)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C1-C4)alkyl.

[0047] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U-, wherein T and U are independently -NH-, -O-, -CHz- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)-, -S(O)2NR'- or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2)s-X- (CH2)t-, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, - S(O)-, -S(O)2-, or -S(0)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted (C1-C6)alkyl.

[0048] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 4 of the ring atoms are a heteroatom each N, O or S. For example, heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any other radicals substituted, especially mono- or di-substituted, by e.g. alkyl, nitro or halogen. Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl represents preferably 2-, 3- or 4-quinolinyl. Isoquinolinyl represents preferably 1-, 3- or 4-isoquinolinyl. Benzopyranyl, benzothiopyranyl represents preferably 3-benzopyranyl or 3-benzothiopyranyl, respectively. Thiazolyl represents preferably 2- or 4-thiazolyl, and most preferred, 4-thiazolyl. Triazolyl is preferably 1-, 2- or 5-(1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl.

[0049] Preferably, heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or any of the radicals substituted, especially mono- or di-substituted.

[0050] As used herein, the term "heteroalkyl" refers to an alkyl group having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heteroalkyl can include ethers, thioethers, alkyl- amines and alkyl-thiols.

[0051] As used herein, the term "heteroalkylene" refers to a heteroalkyl group, as defined above, linking at least two other groups. The two moieties linked to the heteroalkylene can be linked to the same atom or different atoms of the heteroalkylene.

[0052] "Electrophile" refers to an ion or atom or collection of atoms, which may be ionic, having an electrophilic center, i.e., a center that is electron seeking, capable of reacting with a nucleophile. An electrophile (or electrophilic reagent) is a reagent that forms a bond to its reaction partner (the nucleophile) by accepting both bonding electrons from that reaction partner.

[0053] "Nucleophile" refers to an ion or atom or collection of atoms, which may be ionic, having a nucleophilic center, i.e., a center that is seeking an electrophilic center or capable of reacting with an electrophile. A nucleophile (or nucleophilic reagent) is a reagent that forms a bond to its reaction partner (the electrophile) by donating both bonding electrons. A "nucleophilic group" refers to a nucleophile after it has reacted with a reactive group. Non limiting examples include amino, hydroxyl, alkoxy, haloalkoxy and the like.

[0054] For the purpose of this disclosure, "naturally occurring amino acids" found in proteins and polypeptides are L-alanine, L-arginine, L-asparagine, L-aspartic acid, L- cysteine, L-glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L- lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, tyrosine, and or L-valine. ''Non-naturally occurring amino acids" found in proteins are any amino acid other than those recited as naturally occurring amino acids. Non-naturally occurring amino acids include, without limitation, the D isomers of the naturally occurring amino acids, and mixtures of D and L isomers of the naturally occurring amino acids. Other amino acids, such as 4-hydroxyproline, desmosine, isodesmosine, 5-hydroxylysine, epsilon- N-methyllysine, 3-methylhistidine, although found in naturally occurring proteins, are considered to be non-naturally occurring amino acids found in proteins for the purpose of this disclosure as they are generally introduced by means other than ribosomal translation of mRNA.

[0055] "Linear" in reference to the geometry, architecture or overall structure of a polymer, refers to polymer having a single monomer derived backbone.

[0056] "Branched," in reference to the geometry, architecture or overall structure of a polymer, refers to polymer having 2 or more polymer "arms" extending from a single group, such as an L group that may be derived from an initiator employed in an atom transfer radical polymerization reaction. A branched polymer may possess 2 polymer arms, 3 polymer arms, 4 polymer arms, 5 polymer arms, 6 polymer arms, 7 polymer arms, 8 polymer arms ormore. For the purpose of this disclosure, compounds having three or more polymer arms extending from a single linear group are denoted as having a "comb" structure or "comb" architecture.

[0057] Branched can also be achieved through "statistical" structures to create broader dendrimer-like architectures.

[0058] The "biological half-life"of a substance is a pharmacokinetic parameter which specifies the time required for one half of the substance to be removed from an organism following introduction of the substance into the organism.

[0059] An “orthogonal click group” is defined as a pair of chemical functional groups that can participate in a click reaction without interfering with other chemical reactions occurring simultaneously, for example, in a biological system. In some embodiments, orthogonal click group allows for other click chemistry. Compounds

[0060] The compound disclosed herein has the following structure: ); wherein X1, X2, X3, X4, X5, and X6tly H, alkyl, aryl, or halogen; or X3 and X4 together form a saturated or unsaturated 3- to 9- membered carbocyclic ring or heterocyclic ring having one or more heteroatoms selected from N, O, or S; or X5and X4together form a saturated or unsaturated 3- to 9- membered carbocyclic ring or heterocyclic ring having one or more heteroatoms selected from N, O, or S. In some embodiments, the carbocyclic ring and heterocyclic ring may be substituted by halogen.

[0061] In some embodiments, the compound may have the following structure: I); wherein each of X4 and X6 is iC1-C3 alkyl, and halogen. In some embodiments, halogen may be F.

[0062] In the structure (I) or (II) above, Y is L1-L2-L3-Z. In some embodiments, one of L1, L2, and L3 may be absent, therefore Y is L1-L2-Z, L1-L3-Z, or L2-L3-Z. In some embodiments, two of L1, L2, and L3may be absent, therefore Y is L1-Z, L2-Z, or L3-Z. In some embodiments, all of L1, L2, and L3 may be absent, therefore Y is Z.

[0063] When L1is present, L1is selected from the group consisting o ,; R2is H or alkyl; is aryl or heteroaryl; R’ isCH2)b–COOR2, –(CH2)bOH, or –(CH2)b–C(O)NH2, wherein b is 1, 2, or 3; m is an integer between 1 and 15; n is 0, 1, 2, or 3; and z is 1, 2, 3, or 4. In some embodiments, R2is H or C1-3 alkyl. In some embodiments, is C6-C10 aryl or 6-10 membered heteroaryl.

[0065] In some e; wherein z and m are as defined, iments m is an integer between 3 and 12.

[0066] When L2 is present, L2 is selected from the group consisting f , O R' ;4 heteroalkylene, arylene, heteroarylene, or C5 or C6 cycloalkylene; R3is H or alkyl; R5is H, alkyl, is alkyl, optionally substituted aryl or heteroaryl. In some embodC10 aryl or phenyl. In some embodiments, heteroaryl may be 6-10 membered heteroaryl group. In some embodiments, alkyl may be C1-C3 alkyl. In some embodiments, arylene may be C6-C10 arylene. In some embodiments, R4 may be C1-C3 alkyl, phenyl, or CF3substituted phenyl., as

[0069] Z is selected from the group consisting of H, OH, halogen ,; wherein R6), sulfo-NHS, pentafluorophenyl (PFP), 4-nitrophenyl (PNP), 1-Hydroxybenzotriazole (HOBt), 1-Hydroxy- 7-azabenzotriazole (HOAt), and imidazolide esters; X is halogen; a is 0 or 1; and n is as disclosed above ,,; wherein Y’ is H, halogen, SO3H, or SO3Na, and there may be

[0071] In some embodiments, Z may enable further functionalization or linking with another compound or moiety. For example, Z may react with small molecule modulators, peptides, etc. For example, -OH can be configured to react with an acid to form an ester, -NH2 can be configured to react with an acid to form an amide, an acid can be configured to react with an amine to form and amide, an activated acid can be configured to react with an amine to form an amide. In some embodiments, an acid can be configured to react with an alcohol to form an ester, an activated acid can be configured to react with an alcohol to form an ester. In some embodiments, β-CD can be configured to enable self-assembly. In some embodiments, adamentyl can be configured to enable self-assembly. In some embodiments, an orthogonal click group can be configured to undergo a click reaction to link with another compound or moiety.

[0072] In some embodiments of the compound, the compound is selected from the group consisting of:-19-, ,, ,O, , -21-

[0073] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art and are part of routine reaction modification and optimization. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0074] In the schemes shown in the Examples, protecting groups for oxygen atoms are selected for their compatibility with the requisite synthetic steps as well as compatibility of the introduction and deprotection steps with the overall synthetic schemes (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0075] If the compounds of the present technology contain one or more stereogenic centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents or catalysts well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

[0076] The starting materials for the reactions shown in the Examples are generally known or commercial compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0077] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples. The following examples will further describe the present invention, and are used for the purposes of illustration only, and should not be considered as limiting.

[0078] Compounds may be identified by their chemical structure and / or their chemical name. Chemical names were generated using the PerkinElmer (Waltham, MA 02451, USA) ChemDraw®Professional 25.0.2.14 and MestReNova®v15.0.0 (MNova IUPAC Name) nomenclature program. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.

[0079] It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.

[0080] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in their entirety) and the like. All the intermediate compounds of the present invention were used without further purification unless otherwise specified.

[0081] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and / or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety.

[0082] The following example schemes are provided for the guidance of the reader and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase based chemistry, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only and should not be construed as or confused with same numberings in other sections of the application.

[0083] Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot,manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention.

[0084] The following abbreviations have the indicated meanings:

[0085] 2N = a 2 normal solution of a species °C = degree Celsius

[0086] ACN = acetonitrile

[0087] AcOH = acetic acid

[0088] AIBN = azobisisobutyronitrile

[0089] aq. = aqueous

[0090] BINAP = (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl)

[0091] Bn = benzyl

[0092] Boc = tert-butoxycarbonyl

[0093] brine = saturated aqueous solution of sodium chloride (NaCl)

[0094] Bu = butyl

[0095] CD3OD = deuterated methanol

[0096] CHCl3 = chloroform

[0097] CDCl3= deuterochloroform

[0098] CH2Cl2= methylene chloride, or dichloromethane or DCM

[0099] Cs2CO3 = cesium carbonate

[0100] DCC = dicyclohexylcarbodiimide

[0101] DCM = dichloromethane

[0102] DIEA = N,N-diisopropylethylamine

[0103] DMAP = 4-dimethylaminopyridine

[0104] DMF = dimethylformamide

[0105] DMSO = dimethylsulfoxide

[0106] dppf = 1,1’-bis(dipenylphosphino)ferrocene

[0107] EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDC·HCl, EDAC)

[0108] Et = ethyl

[0170] TLC thin layer chromatography

[0171] TMA = trimethlyamine

[0172] TMS = trimethylsilyl

[0173] wt% = weight percentage EXAMPLES

[0174] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. Example 1: 7,8-Didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonineStep 1: Synthesis of but-2-yne-1,4-diol cobalt complex

[0175] To a stirred mixture of but-2-yne-1,4-diol (10.0 g, 116.0 mmol) in CH2Cl2 (4.0 L) was added dicobalt octacarbonyl (41.7 g, 122.1 mmol) in portions at rt. The resulting mixture was stirred at rt overnight. The reaction mixture was then concentrated by rotaryevaporation under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / EA gradients (0~30%) to afford but-2-yne-1,4-diol cobalt complex as a brownish solid (36.0 g, 83% yield).

[0176] 1H NMR (400 MHz, CDCl3) δ 4.86 (s, 4H), 2.54 (s, 2H) ppm. Step 2: Synthesis of N-(3-hydroxypropyl)-2-nitrobenzenesulfonamide

[0177] To a solution of 3-aminopropan-1-ol (10.0 g, 133.1 mmol) in anhydrous CH2Cl2(500 mL) was added pyridine (21.0 g, 266.2 mmol) and 2-nitrobenzenesulfonyl chloride (35.4 g, 159.7 mmol) in portions at 0 °C under an atmosphere of N2. The resulting mixture was stirred at 0~5 °C for 1 hour. The reaction mixture was then concentrated by rotary evaporation under reduced pressure and the residue was subjected to silica gel column chromatography purification eluting with CH2Cl2 / MeOH (0-1%) to afford N-(3- hydroxypropyl)-2-nitrobenzenesulfonamide as a pale-yellow oil (10.6 g, 30% yield).

[0178] 1H NMR (400 MHz, CD3OD) δ 8.12 – 8.04 (m, 1H), 7.89 – 7.84 (m, 1H), 7.83 – 7.78 (m, 2H), 3.58 (t, J = 6.1 Hz, 2H), 3.14 (t, J = 6.9 Hz, 2H), 1.71 (p, J = 6.5 Hz, 2H) ppm.

[0179] LC / MS: mass calcd for C9H12N2O5S: 260.05, found: m / z = 260.90 [M+H]+. Step 3: Synthesis of 5-[(2-Nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5- oxazonine cobalt complex

[0180] To a mixture of N-(3-hydroxypropyl)-2-nitrobenzenesulfonamide (10.6 g, 40.7 mmol) and but-2-yne-1,4-diol cobalt complex (11.5 g, 30.9 mmol) in anhydrous CH2Cl2(2.0 L) was added boron trifluoride diethyl etherate (10.5 g, 74.0 mmol) in portions at 0 °C under an atmosphere of N2. The resulting mixture was allowed to warm to rt and stirred for 1 hour. The reaction was quenched by sat. NaHCO3aq. solution (500 mL) and the resulting mixture was extracted with CH2Cl2 (3 x 500 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2to afford 5-[(2- nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine cobalt complex as a dark-brown solid (14.0 g, 76%).

[0181] 1H NMR (400 MHz, CD3OD) δ 8.08 – 8.04 (m, 1H), 7.88 – 7.79 (m, 3H), 5.04 (s, 2H), 4.85 (s, 2H), 3.94 (t, J = 5.4 Hz, 2H), 3.57 (t, J = 5.9 Hz, 2H), 2.05 – 1.96 (m, 2H) ppm.Step 4: Synthesis of 5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5- oxazonine

[0182] To a stirred mixture of 5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro- 2,3,4,5,6,9-hexahydro-1,5-oxazonine cobalt complex (5 g, 8.4 mmol) in anhydrous CH2Cl2 (1.0 L) was added ceric ammonium nitrate (25.6 g, 46.7 mmol) and silica gel (100.0 g, 100~200 mesh) in portions at rt. The resulting mixture was allowed to stir at rt for 16 h. The mixture was then filtered through silica gel, washed with 25% EA in CH2Cl2. The filtrate was concentrated by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography eluting with Hex / EA gradients (10~30%) to afford 5-[(2- nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine as a white solid (1.2 g, 46%).

[0183] 1H NMR (400 MHz, CDCl3) δ 8.03 – 7.96 (m, 1H), 7.78 – 7.67 (m, 2H), 7.66 – 7.61 (m, 1H), 4.15 – 4.08 (m, 4H), 3.87 (t, J = 5.3 Hz, 2H), 3.53 (t, J = 5.6 Hz, 2H), 1.96 (p, J = 5.4 Hz, 2H) ppm.

[0184] LC / MS: mass calcd for C13H14N2O5S: 310.06, found: m / z = 310.85 [M+H]+. Step 5: Synthesis of 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine

[0185] To a stirred mixture of 5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro- 2,3,4,5,6,9-hexahydro-1,5-oxazonine (1.0 g, 3.2 mmol) in anhydrous ACN (20.0 mL) was added Cs2CO3(3.2 g, 9.8 mmol) and p-toluenethiol (1.2 g, 9.7 mmol) in portions at rt. The reaction mixture was stirred at rt for 16 h under an atmosphere of N2. The mixture was diluted with diethyl ether (30 mL). Then the pH of the mixture was adjusted to 2~3 with 1N HCl solution (~30 mL). The resulting mixture was extracted with diethyl ether (3 x 30 mL). The aqueous layer was basified to pH 13~14 and extracted with CH2Cl2 (3 x 30 mL). All organic layers were combined, dried over Na2SO4, and concentrated by rotary evaporation under reduced pressure to afford 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (300 mg, 74%) as a dark-brownish solid.

[0186] 1H NMR (400 MHz, CDCl3) δ 4.18 – 4.11 (m, 2H), 3.90 – 3.82 (m, 2H), 3.47 – 3.40 (m, 2H), 3.05 – 2.97 (m, 2H), 1.84 – 1.67 (m, 2H) ppm. Example 2: 7,8-Didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic saltStep 1: Synthesis of 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic acid salt

[0187] To a stirred mixture of 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (300 mg, 2.4 mmol) in anhydrous MeOH (3.0 mL) was added a solution of oxalic acid (216 mg, 2.4 mmol) in MeOH (2.0 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 minutes under an atmosphere of N2. The mixture was filtered through a Celite®cake and washed with MeOH (2 x 5 mL). The filtrate was concentrated by rotary evaporation under reduced pressure to afford 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5- oxazonine oxalic acid salt as a white solid (390 mg, 76%).

[0188] 1H NMR (400 MHz, D2O) δ 4.29 – 4.23 (m, 2H), 3.99 – 3.91 (m, 4H), 3.53 – 3.45 (m, 2H), 2.12 – 2.02 (m, 2H). Example 3: Intermediate 1: (S)-3-((tert-butoxycarbonyl)amino)-3-carboxypropyl (2- (trimethylammonio)ethyl) phosphate.Scheme:Nyl)-L-homoserinate.

[0189] To a dried and nitrogen-purged flask was added benzyl (tert- butoxycarbonyl)-L-homoserinate (2.0 g, 6.5 mmol) in anhydrous THF (20 mL). The flask was evacuated and refilled with N2 three times. TEA (2.6 g, 25.9 mmol) was added via a syringe. The reaction mixture was cooled to -78 °C using a dry ice / acetone bath, and 2-chloro-1,3,2- dioxaphospholane 2-oxide (3.7 g, 25.9 mmol) was added dropwise. The mixture was stirred at -78 °C for 2 h, during which TLC indicated completion of the reaction. The mixture was filtered through a Celite pad and eluted with EA (20 mL). The filtrate was directly purified on a silica gel chromatography column, eluting with 100% EA to afford benzyl N-(tert- butoxycarbonyl)-O-(2-oxido-1,3,2-dioxaphospholan-2-yl)-L-homoserinate as a pale-yellow oil (2.6 g, 96.8% yield).

[0190] 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 4H), 5.17 (s, 2H), 4.50 – 4.31 (m, 5H), 4.27 – 4.17 (m, 2H), 2.33 – 2.21 (m, 1H), 2.17 – 2.07 (m, 1H), 1.43 (s, 9H) ppm. Step 2: Synthesis of (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl (2- (trimethylammonio)ethyl) phosphate.

[0191] Benzyl N-(tert-butoxycarbonyl)-O-(2-oxido-1,3,2-dioxaphospholan-2-yl)- L-homoserinatev (2.6 g, 6.3 mmol) was dissolved in anhydrous ACN (5.2 mL), then TMA (38 mL, 76.0 mmol, 2.0 N in ACN) was added. The reactor was purged with N2, sealed, and then heated in an oil bath at 70 °C with stirring for 16 h. The progress of the reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was filtered through a Celite pad andwashed with ACN (50 mL). The filtrate was evaporated to dryness under reduced pressure. The resulting solid residue was triturated with PE (10 mL) at rt for 1 h, filtered, and the solid was collected and dried to afford (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4- oxobutyl (2-(trimethylammonio)ethyl) phosphate as a pale-yellow solid (2.1 g, 74.1% yield).

[0192] LC / MS: mass calcd for C21H35N2O8P: 474.21, found: m / z = 475.05 [M+H]+.

[0193] 1H NMR (400 MHz, D2O) δ 7.46 (s, 5H), 5.25 (s, 2H), 4.34 – 4.21 (m, 3H), 4.06 – 3.86 (m, 3H), 3.55 (s, 2H), 3.16 (s, 9H), 2.26 – 2.16 (m, 1H), 2.06 – 1.97 (m, 1H), 1.49 – 1.28 (m, 9H) ppm. Step 3: Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-3-carboxypropyl (2- (trimethylammonio)ethyl) phosphate

[0194] To a solution of (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4- oxobutyl (2-(trimethylammonio)ethyl) phosphate (600.2 mg, 1.3 mmol) in MeOH (6 mL) was added Pd / C (60 mg, 10%) under a nitrogen atmosphere. The mixture was purged with H2and stirred at 35 °C for 2 h under an atmosphere of H2 (1 atm). The mixture was cooled to rt, filtered through a Celite cake, and washed with CH3OH (20 mL). The filtrate was concentrated under reduced pressure by rotary evaporation to afford (S)-3-((tert-butoxycarbonyl)amino)-3- carboxypropyl (2-(trimethylammonio)ethyl) phosphate as a grey solid (480.0 mg, 99.3% yield).

[0195] 1H NMR (400 MHz, D2O) δ 4.19 – 4.13 (m, 2H), 3.91 – 3.78 (m, 3H), 3.56 – 3.49 (m, 2H), 3.08 (s, 9H), 2.07 – 1.91 (m, 1H), 1.83 – 1.70 (m, 1H), 1.29 (s, 9H) ppm. Example 4: Synthesis of 3-methyl-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine.Scheme

[0196] 3-Amino-2-methylpropan-1-ol (2.5 g, 28.1 mmol) was dissolved in CH2Cl2(50 mL) in a single-neck flask. The reaction mixture was purged with N2 (3 cycles) and cooled to 0 °C using an ice / water bath, before the dropwise addition of 2-nitrobenzenesulfonyl chloride (4.4 g, 19.6 mmol). The reaction mixture was stirred at 0 °C for 1 h, while being monitored with TLC. Once the reaction was completed, 2 mL of CH3OH was added, and the resulting crude mixture was subjected to silica gel column chromatography purification eluting with CH3OH / CH2Cl2gradients (0-5%) to afford N-(3-hydroxy-2-methylpropyl)-2- nitrobenzenesulfonamide as a pale-yellow oil (4.0 g, 73.4% yield).

[0197] LC-MS: mass calcd for C10H14N2O5S: 274.06, found: m / z = 275.16 [M+H]+. Step 2: Synthesis of 3-methyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine cobalt carbonyl complex.

[0198] N-(3-Hydroxy-2-methylpropyl)-2-nitrobenzenesulfonamide (4.9 g, 13.3 mmol) and but-2-yne-1,4-diol cobalt carbonyl complex (4.0 g, 14.6 mmol) were dissolved in CH2Cl2 (1 L) in a single-neck flask, before the addition of BF3•Et2O (3.8 g, 26.5 mmol). The reaction mixture was stirred at rt for 1 h, while being monitored by TLC. Once the reaction was completed, NaHCO3(aq., sat.) was added, and the collected organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The resulting crude mixture was subjected to silica gel column chromatography purification eluting with 100% CH2Cl2to afford 3-methyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine cobalt carbonyl complex as a brownish solid (5.6 g, 69.7% yield). LC-MS: mass calcd for C20H16Co2N2O11S: 609.91, found: m / z = 610.88 [M+H]+. Step 3: Synthesis of 3-methyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine.

[0199] 3-Methyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine cobalt carbonyl complex (300 mg, 0.5 mmol) was dissolved in CH2Cl2 (60 mL) in a single-neck flask, before the addition of CAN (1.4 g, 2.5 mmol) and silica gel (3.0 g). The mixture was allowed to stir at rt overnight while open to air. Once the reaction was completed, the mixture was filtered through silica gel, and washed with CH2Cl2(10 mL). The filtrate was concentrated by rotary evaporation under reduced pressure to afford 3-methyl- 5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine as a pale yellow solid (90.2 mg, 56.4% yield).

[0200] LC-MS: mass calcd for C14H16N2O5S: 324.08, found: m / z = 325.09 [M+H]+. Step 4: Synthesis of 3-methyl-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine.

[0201] 3-Methyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine (90.2 mg, 0.3 mmol) was dissolved in ACN (4 mL) in a single-neck flask, before the addition of Cs2CO3(271.2 mg, 0.8 mmol), 4-methylbenzenethiol (103.4 mg, 0.8 mmol) under N2atmosphere. The resulting mixture was stirred at rt overnight. After overnight reaction, the mixture was diluted with 30 mL of Et2O, HCl (1M) 30 mL. The aqueous layer was extracted with Et2O (2 x 20 mL). The aqueous layer was then collected, and its pH was adjusted to ~13-14 using NaOH (1 M), then extracted with CH2Cl2(3 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford 3-methyl-7,8-didehydro-2,3,4,5,6,9-hexahydro- 1,5-oxazonine as a yellow oil (26.4 mg, 67.3% yield).

[0202] 1H NMR (400 MHz, CDCl3) δ 4.19 – 4.05 (m, 2H), 3.79 (dd, J = 11.9, 3.2 Hz, 1H), 3.68 (dd, J = 11.8, 6.2 Hz, 1H), 3.47 – 3.41 (m, 2H), 2.95 (dd, J = 13.7, 3.7 Hz, 1H), 2.85 (dd, J = 13.7, 7.5 Hz, 1H), 1.85 – 1.73 (m, 1H), 0.90 (d, J = 7.2 Hz, 3H) ppm. Example 5: Synthesis of 3,3-dimethyl-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine.Step 1: Synthesis of N-(3-hydroxy-2,2-dimethylpropyl)-2-nitrobenzenesulfonamide.

[0203] In a 250 mL RBF, 3-amino-2,2-dimethylpropan-1-ol (0.8 g, 10.0 mmol) was dissolved in CH2Cl2 (45 mL) at 0 °C, before the dropwise addition of a solution of 2- nitrobenzenesulfonyl chloride (1.1 g, 5.0 mmol) in CH2Cl2 (5 mL). The mixture was stirred at 0 °C, and slowly warmed to room temperature, while being monitored by TLC. Once the reaction was completed, the mixture was concentrated by rotary evaporation under reduced pressure. The crude was mixed with 30 mL of HCl (1M, aq.), and extracted with EA (3 x 30 mL). The combined organic layer was washed with sat. NaHCO3(aq., 30 mL), sat. brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford N-(3-hydroxy-2,2-dimethylpropyl)-2-nitrobenzenesulfonamide as a colorless oil (1.4 g, 97.8% yield).

[0204] MS: mass calcd for C11H16N2O5S: 288.08, found: m / z = 289.14 [M+H]+

[0205] 1H NMR (600 MHz, CDCl3) δ 8.16 – 8.10 (m, 1H), 7.89 – 7.84 (m, 1H), 7.78 – 7.71 (m, 2H), 5.82 (t, J = 6.6 Hz, 1H), 3.44 (s, 2H), 2.95 (d, J = 6.6 Hz, 2H), 0.91 (s, 6H) ppm. Step 2: Synthesis of 3,3-dimethyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine cobalt carbonyl complex.

[0206] In a 500 mL RBF, N-(3-hydroxy-2,2-dimethylpropyl)-2- nitrobenzenesulfonamide (1.4 g, 4.9 mmol), but-2-yne-1,4-diol cobalt carbonyl complex (1.8 g, 4.9 mmol) were dissolved in of CH2Cl2(5 mL) at 0 °C, before the dropwise addition of BF3•Et2O (1.2 mL, 9.7 mmol). The mixture was slowly warmed to rt for 3 h. The reaction was monitored by TLC. Once the reaction was completed, the mixture was quenched with sat. NaHCO3(aq., 30 mL) and concentrated by rotary evaporation under reduced pressure. The residue was extracted with CH2Cl2(30 mL x 5). The combined organic layer was washed with sat. brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation under reduced pressure, and purified by silica gel column chromatography purification eluting with EA / Hex gradients (0-40%) to afford 3,3-dimethyl-5-[(2-nitrophenyl)sulfonyl]-7,8- didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine cobalt carbonyl complex as a brownish solid (410.2 mg, 13.5% yield).

[0207] MS: mass calcd for C21H18Co2N2O11S: 623.93, found: m / z = 624.90 [M+H]+

[0208] 1H NMR (600 MHz, CDCl3) δ 8.07 (br s, 1H), 7.89 – 7.58 (m, 3H), 5.07 – 4.68 (m, 4H), 3.67 – 3.20 (m, 4H), 0.97 (s, 6H) ppm. Step 3: Synthesis of 3,3-dimethyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine.

[0209] In a 250 mL RBF, 3,3-dimethyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro- 2,3,4,5,6,9-hexahydro-1,5-oxazonine cobalt carbonyl complex (410.2 mg, 0.7 mmol) was dissolved in CH2Cl2 (150 mL), then CAN (1.8 g, 3.3 mmol) and silica gel (10.0 g) were added. The mixture was allowed to stir at rt while open to air, while the reaction was monitored by TLC. Once the reaction was completed, the mixture was filtered through silica gel, and washed with CH2Cl2 (50 mL). The filtrate was concentrated by rotary evaporation under reduced pressure to afford 3,3-dimethyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine as a pale-yellow solid (73.1 mg, 32.8% yield).

[0210] MS: mass calcd for C15H18N2O5S: 338.09, found: m / z = 339.06 [M+H]+

[0211] 1H NMR (600 MHz, CDCl3) δ 7.94 (dd, J = 7.7, 1.6 Hz, 1H), 7.77 – 7.67 (m, 2H), 7.62 (dd, J = 7.5, 1.6 Hz, 1H), 4.10 (t, J = 2.6 Hz, 2H), 3.89 (s, 2H), 3.61 – 3.46 (m, 2H), 3.38 (s, 2H), 0.93 (s, 6H) ppm. Step 4: Synthesis of 3,3-dimethyl-7,8-didehydro-234569-hexahydro-1,5-oxazonine.

[0212] In a 100 mL RBF, 3,3-dimethyl-5-[(2-nitrophenyl)sulfonyl]-7,8-didehydro- 2,3,4,5,6,9-hexahydro-1,5-oxazonine (300.0 mg, 0.9 mmol) was dissolved in ACN (20 mL), before the addition of Cs2CO3(866.2 mg, 2.7 mmol). Then 4-methylbenzenethiol (330.7 mg, 2.7 mmol) was added into the mixture under N2 atmosphere. The resulting mixture was stirred at rt overnight. After overnight reaction, the mixture was diluted with Et2O (50 mL), and the pH was adjusted to ~ 2-3 using HCl (1M). The aqueous layer was extracted again with Et2O (20 mL x 2). The aqueous layer was collected, and its pH was adjusted to ~13-14 using NaOH (0.5 M), then extracted with CH2Cl2 (30 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford the 3,3-dimethyl-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine neutral amine as a pale-yellow oil (111.4 mg, 81.7% yield).

[0213] MS: mass calcd for C9H15NO: 153.12, found: m / z = 154.20 [M+H]+

[0214] 1H NMR (600 MHz, CDCl3) δ 4.07 (s, 1H), 4.01 (s, 1H), 3.75 (s, 1H), 3.38 (s, 2H), 3.25 (s, 1H), 2.89 (s, 1H), 2.55 (s, 1H), 2.08 (s, 1H), 0.83 (s, 3H), 0.73 (s, 3H) ppm. Example 6: Synthesis of 3,3-difluoro-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine.Step 1: Synthesis of N-(2,2-difluoro-3-hydroxypropyl)-4-methylbenzenesulfonamide.

[0215] In a 100 mL RBF, 3-amino-2,2-difluoropropan-1-ol (1.0 g, 9.0 mmol) was dissolved in CH2Cl2 (50 mL) at 0 °C, before the dropwise addition of 4-methylbenzenesulfonyl chloride (1.4 g, 7.2 mmol) in CH2Cl2(5 mL). The mixture was stirred at 0 °C, and slowly warmed to room temperature, while being monitored by TLC. Once the reaction was completed, the mixture was concentrated by rotary evaporation under reduced pressure. The crude was mixed with 30 mL of HCl (1M, aq.) and extracted with EA (3 x 30 mL). The combined organic layers were washed with sat. NaHCO3(aq., 30 mL), sat. brine (aq., 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford N-(2,2-difluoro-3-hydroxypropyl)-4-methylbenzenesulfonamide as a colorless oil (1.1 g, 56.5% yield). Step 2: Synthesis of 3,3-difluoro-5-[(4-methylphenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine cobalt carbonyl complex.

[0216] N-(2,2-Difluoro-3-hydroxypropyl)-4-methylbenzenesulfonamide (1.1 g, 4.1 mmol), but-2-yne-1,4-diol cobalt carbonyl complex (1.7 g, 4.5 mmol) were dissolved in CH2Cl2 (1 L) at 0 °C, before the dropwise addition of BF3•Et2O (1.2 g, 8.2 mmol). The mixture was slowly warmed to rt for 1 h. The reaction was monitored by TLC. Once the reaction was completed, the mixture was quenched with sat. NaHCO3(aq., 200 mL) and concentrated by rotary evaporation under reduced pressure. The residue was extracted with CH2Cl2 (3 x 300 mL). The combined organic layers were washed with sat. brine (aq., 30 mL), dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation under reduced pressure, and purified by silica gel column chromatography purification eluting with EA / Hex gradients (0- 40%) to afford 3,3-difluoro-5-[(4-methylphenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine cobalt carbonyl complex as a brownish solid (0.9 g, 36.0% yield).

[0217] LC-MS: mass calcd for C20H15Co2F2NO9S: 600.91, found: m / z = 601.91 [M+H]+. Step 3: Synthesis of 3,3-difluoro-5-[(4-methylphenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine

[0218] 3,3-Difluoro-5-[(4-methylphenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine cobalt carbonyl complex (0.9 g, 1.5 mmol) was dissolved in CH2Cl2(60 mL). CAN (3.9 g, 7.5 mmol) and silica gel (9.0 g) were added. The mixture was stirred at rt while open to air. And the reaction was monitored by TLC. Once the reaction was completed,the mixture was filtered through silica gel and washed with CH2Cl2 (100 mL). The filtrate was concentrated by rotary evaporation under reduced pressure to afford 3,3-difluoro-5-[(4- methylphenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine as a white solid (430.1 mg, 91.0% yield).

[0219] LC-MS: mass calcd for C14H15F2NO3S: 315.07, found: m / z = 316.03 [M+H]+. Step 4: Synthesis of 3,3-difluoro-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine.

[0220] 3,3-Difluoro-5-[(4-methylphenyl)sulfonyl]-7,8-didehydro-2,3,4,5,6,9- hexahydro-1,5-oxazonine (150.0 mg, 0.5 mmol) was dissolved in THF (30 mL), and purged with N2 / vacuum (3 cycles) at -78 °C. Sodium / naphthalide solution (0.2 M) was dropwise added into the reaction mixture, until no color change after addition. Once the reaction was completed, the mixture was diluted with Et2O (30 mL) and 1M HCl (aq., 30 mL). The pH of the collected aqueous layer was adjusted to ~14 with 1M NaOH (aq.) and extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford the 3,3-difluoro-7,8- didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine as a yellow oil (36.3 mg, 46.0% yield).

[0221] LC-MS: mass calcd for C7H9F2NO: 161.07, found: m / z = 162.13 [M+H]+

[0222] 1H NMR (400 MHz, CDCl3) δ 4.23 (d, J = 2.6 Hz, 2H), 4.05 (t, J = 12.2 Hz, 2H), 3.54 (s, 2H), 3.40 – 3.27 (m, 2H). Example 7: Synthesis of 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine 4- methylbenzenesulfonic acid salt.Step 1: Synthesis of 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine 4- methylbenzenesulfonic acid salt.

[0223] 7,8-Didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (100.0 mg, 0.8 mmol) was dissolved in EA (3 mL). Separately, 4-methylbenzenesulfonic acid (137.6 mg, 0.8 mmol) was dissolved in EA (3 mL). The acid solution was added dropwise to the solution of 7,8- didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine, until a white solid precipitated. The suspension was filtered, and the solid was washed with EA (2 mL) to give 7,8-didehydro- 2,3,4,5,6,9-hexahydro-1,5-oxazonine 4-methylbenzenesulfonic acid salt as a white solid (200.5 mg, 84.1% yield).

[0224] 1H NMR (400 MHz, D2O) δ 7.51 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 4.05 (t, J = 2.4 Hz, 2H), 3.77 – 3.71 (m, 4H), 3.30 – 3.24 (m, 2H), 2.21 (s, 3H), 1.90 – 1.82 (m, 2H) ppm. Example 8: Synthesis of 3-methyl-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic acid salt. SchemeStep 1: Synthesis of 3-methyl-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic acid salt.

[0225] 3-Methyl-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (190.2 mg, 1.4 mmol) was dissolved in MeOH (2 mL) in a single-neck flask, before the dropwise addition of oxalic acid solution (123.0 mg, 1.4 mmol, in 1 mL MeOH). The reaction mixture was filtered and washed with EA. The resulting solid was dried under vacuum to afford the 3-methyl-7,8- didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic acid salt as a white solid (205.9 mg, 70.0% yield).

[0226] 1H NMR (400 MHz, CD3OD) δ 4.27 – 4.09 (m, 2H), 3.93 (t, J = 2.4 Hz, 2H), 3.88 (dd, J = 12.7, 3.1 Hz, 1H), 3.72 (dd, J = 12.7, 5.7 Hz, 1H), 3.38 – 3.32 (m, 1H), 3.30 – 3.25 (m, 1H), 2.25 – 2.10 (m, 1H), 1.03 (d, J = 7.1 Hz, 3H) ppm. Example 9: Synthesis of 3,3-difluoro-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic acid salt. Scheme:OH O O OH O FStep 1: Synthesis of 3,3-difluoro-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic acid salt.

[0227] 3,3-Difluoro-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (78.0 mg, 0.5 mmol) was dissolved in MeOH (1 mL) in a single-neck flask, before the dropwise addition of oxalic acid solution (44.2 mg, 0.5 mmol) in MeOH (1 mL). The reaction mixture was filtered and washed with EA. The resulting solid was dried under vacuum to afford the 3,3-difluoro-7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine oxalic acid salt as a white solid (59.0 mg, 48.0% yield).

[0228] 1H NMR (400 MHz, CD3OD) δ 4.31 (t, J = 2.4 Hz, 2H), 4.15 (t, J = 12.6 Hz, 2H), 3.97 (t, J.2 Hz, 2H) ppm.

[0229] 19F NMR (376 MHz, CD3OD) δ -115.18 ppm. Example 10 : Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoic acid.Scheme: Step 1: Synthe -oxazonin-5(2H)-yl]-4- oxobutanoic acid.

[0230] In a 100 mL round bottom flask, 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5- oxazonine (260.0 mg, 2.1 mmol), succinic anhydride (416.0 mg, 4.2 mmol) were dissolved in CH2Cl2(10 mL), before the addition of TEA (1.2 mL, 8.4 mmol). The resulting mixture was allowed to stir at rt for 2 hours. The mixture was concentrated by rotary evaporation under reduced pressure, and re-dissolved in 1 M HCl (aq., 30 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude was further purified with silica gel column chromatography purification eluting with CH3OH / CH2Cl2 gradients (0-7%) to afford 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoic acid as a pale yellowish solid (382.3 mg, 82.0% yield). 1H NMR (600 MHz, CD3OD) δ 4.24 (dt, J = 8.9, 2.5 Hz, 2H), 4.16 – 4.10 (m, 2H), 3.86 – 3.80 (m, 1H), 3.79 – 3.75 (m, 1H), 3.74 – 3.69 (m, 1H), 3.62 – 3.57 (m, 1H), 2.69 – 2.62 (m, 3H), 2.61 – 2.57 (m, 1H), 2.07 – 2.01 (m, 1H), 1.95 – 1.88 (m, 1H) ppm. Example 11: Synthesis of 3-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoic acidStep 1: Synthesis of methyl 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoate

[0231] To a solution of 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (350.0 mg, 2.8 mmol) in anhydrous THF (500 mL) was added methyl 3-(chlorosulfonyl)propanoate (783.0 mg, 4.2 mmol) and TEA (566.1 mg, 5.6 mmol) in portions at 0 °C under an atmosphere N2. The resulting mixture was allowed to warm to rt and stirred for 2 h. The mixture was concentrated by rotary evaporation under reduced pressure and the residue was purified by silica gel column chromatography eluting with MeOH / CH2Cl2 gradients (0~1%) to afford methyl 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-ylsulfonyl]propanoate as a white solid (430.5 mg, 56.2 % yield).

[0232] 1H NMR (400 MHz, CDCl3) δ 4.13 (t, J = 2.4 Hz, 2H), 3.99 (t, J = 2.4 Hz, 2H), 3.92 – 3.82 (m, 2H), 3.74 (s, 3H), 3.55 – 3.48 (m, 2H), 3.29 (dd, J = 7.9, 7.1 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 1.95 – 1.85 (m, 2H) ppm. Step 2: Synthesis of 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoic acid

[0233] To a solution of methyl 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-ylsulfonyl]propanoate (430.0 mg, 1.6 mmol) in THF (5 mL) and MeOH (5 mL) was added a solution of LiOH monohydrate (263.2 mg, 6.3 mmol) in water (2 mL) in portions at 0 °C. The resulting mixture was allowed to warm to rt and stirred for 2 h. Then the pH of the mixture was adjusted to 2~3 with 2N HCl solution and the resulting mixture was extracted with EA (3 x 500 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford 3-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-ylsulfonyl]propanoic acid as a white solid (150.2 mg, 37.4% yield).

[0234] 1H NMR (400 MHz, CD3OD) δ 4.16 – 4.11 (m, 2H), 4.03 – 3.99 (m, 2H), 3.87 (t, J = 5.2 Hz, 2H), 3.50 (t, J = 5.6 Hz, 2H), 3.37 (t, J = 7.3 Hz, 2H), 2.76 (t, J = 7.3 Hz, 2H), 1.88 – 1.83 (m, 2H) ppm. Example 12: Synthesis of 4-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylcarbonyl]benzoic acidScheme:Step 1: Synthesis of 4-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylcarbonyl]benzoic acid

[0235] 7,8-Didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (110.0 mg, 0.9 mmol), 4-(chlorocarbonyl)benzoic acid (100.0 mg, 0.5 mmol) were dissolved in CH2Cl2(10 mL), before the addition of TEA (0.7 ml, 5.3 mmol). The resulting solution was stirred at rt for 2 hours. The crude mixture was concentrated by rotary evaporation under reduced pressure, then redissolved in 1 M HCl (aq., 20 mL). The resulting solution was extracted with EA (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude was further purified with silica gel column chromatography purification eluting with MeOH / CH2Cl2gradients (0- 10%) to afford the 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylcarbonyl]benzoic acid as a pale yellow solid (120.1 mg, 81.3% yield).

[0236] 1H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 4.17 (s, 2H), 4.01 (s, 2H), 3.90 (t, J = 5.3 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 2.18 – 2.13 (m, 2H) ppm. Example 13: Synthesis of 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoate.O-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoate.

[0237] In a 100 mL round bottom flask, 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoic acid (200.0 mg, 0.89 mmol), N, N′-disuccinimidyl carbonate (341.1 mg, 1.3 mmol) were dissolved in CH2Cl2 (10 mL), before the addition of DIEA (0.23 ml, 1.3 mmol). The resulting mixture was allowed to stir at rt for 1 hour. The mixture was concentrated by rotary evaporation under reduced pressure, then further purified with silica gel column chromatography purification eluting with EA / Hexane gradients (50- 100%) to afford 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-oxobutanoate as a white solid (260.1 mg, 90.2% yield).

[0238] 1H NMR (600 MHz, CDCl3) δ 4.21 (t, J = 2.6 Hz, 1H), 4.11 – 3.99 (m, 3H), 3.78 – 3.64 (m, 2H), 3.61 – 3.47 (m, 2H), 2.97 – 2.85 (m, 2H), 2.76 (s, 4H), 2.68 (t, J = 6.7 Hz, 2H), 1.94 – 1.85 (m, 2H) ppm. Example 14: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl chloride.Step 1: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl chloride.

[0239] 4-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoic acid (50.0 mg, 0.2 mmol) was dissolved in CH2Cl2 (2 mL) in a single-necked flask. To this solution at 0 °C were added oxalyl chloride (56.3 mg, 0.4 mmol) and DMF (0.2 mL) dropwise. The mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to afford 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl chloride as a yellow solid (60.2 mg, 111.1 % yield).

[0240] 1H NMR (400 MHz, DMSO-d6) δ 4.18 – 4.13 (m, 2H), 4.10 – 4.05 (m, 2H), 3.72 – 3.59 (m, 2H), 3.54 – 3.36 (m, 2H), 2.53 – 2.48 (m, 2H), 2.44 – 2.35 (m, 2H), 1.91 – 1.67 (m, 2H) ppm. Example 15: Synthesis of 2,5-dioxopyrrolidin-1-yl 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-ylsulfonyl]propanoate.Step 1: Synthesis of 2,5-dioxopyrrolidin-1-yl 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-ylsulfonyl]propanoate.

[0241] 3-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoic acid (330.0 mg, 1.3 mmol) and EDCI (290.2 mg, 1.5 mmol) were dissolved in DMF (5 mL). After purging with N2, the mixture was cooled in an ice-water bath to 0-5 °C, and N-hydroxysuccinimide (110.4 mg, 1.5 mmol) was added. The reaction mixturewas stirred at rt for 2 h, and the mixture was concentrated to dryness. The residue was dissolved in CH2Cl2 (10 mL), and purified by a silica gel column, eluting with 100% CH2Cl2 to afford 2,5-dioxopyrrolidin-1-yl 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoate as a colorless oil (250.8 mg, 55.2% yield).

[0242] 1H NMR (400 MHz, CDCl3) δ 4.14 (t, J = 2.4 Hz, 2H), 4.02 (d, J = 2.4 Hz, 2H), 3.88 (t, J = 5.3 Hz, 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.34 (dd, J = 8.2, 6.8 Hz, 2H), 3.17 (t, J = 7.5 Hz, 2H), 2.86 (s, 4H), 1.97 – 1.89 (m, 2H) ppm. Example 16: Synthesis of 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl chlorideSchemeStepy , y , , , trahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl chloride.

[0243] 3-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoic acid (30.0 mg, 0.1 mmol) was dissolved in CH2Cl2 (2 mL) in a single- necked flask. DMF (2 drops) was added, and the flask was purged with N2 three times. At 0 °C, oxalyl chloride (29.1 mg, 0.2 mmol) in CH2Cl2(1 mL) was added in a dropwise manner. The mixture was stirred at rt for 2 h, and the mixture was directly concentrated under reduced pressure to afford 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl chloride as a yellow solid (35.8 mg, 111.5% yield).

[0244] 1H NMR (400 MHz, CDCl3) δ 4.13 (d, J = 2.6 Hz, 2H), 4.01 – 3.97 (m, 2H), 3.88 (t, J = 5.2 Hz, 2H), 3.57 – 3.50 (m, 2H), 3.43 (t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H), 1.91 (p, J = 5.3 Hz, 2H) ppm.Example 17: Synthesis of 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-ylcarbonyl]benzoate.oxazonin-5(2H)-ylcarbonyl]benzoate.

[0245] 4-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylcarbonyl]benzoic acid (20.5 mg, 0.07 mmol), TSTU (24.0 mg, 0.08 mmol) were mixed with CH2Cl2(2 mL), before the addition of DIEA (0.1 ml, 0.6 mmol). The mixture was allowed to stir at rt for 3 hours. The crude mixture was concentrated by rotary evaporation under reduced pressure, then further purified with silica gel column chromatography purification eluting with EA / Hexane gradients (50-80%) to afford the product as a white solid (7.2 mg, 26.3% yield).

[0246] 1H NMR (600 MHz, CDCl3) δ 8.24 – 8.18 (m, 2H), 7.62 – 7.52 (m, 2H), 4.48 – 4.17 (m, 2H), 4.16 – 3.95 (m, 2H), 3.92 – 3.49 (m, 4H), 2.93 (s, 4H), 2.16 – 1.75 (m, 2H) ppm. Example 18: Synthesis of 3-amino-1-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]propan-1-one. SchemeStep 1: Synthesis of tert-butyl {3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]- 3-oxopropyl}carbamate.

[0247] In a RBF, 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (301.0 mg, 2.4 mmol), 2,5-dioxopyrrolidin-1-yl 3-((tert-butoxycarbonyl)amino)propanoate (796.0 mg, 2.8 mmol), TEA (1.6 mL, 12.0 mmol) were dissolved in CH2Cl2(10 mL). The mixture was allowed to stir at rt for 2 h, while being monitored using TLC. Once the reaction was completed, the mixture was concentrated by rotary evaporation under reduced pressure. The crude was diluted with EA (30 mL), and washed with 1M HCl (aq., 30 mL), sat. NaHCO3 (aq., 30 mL), sat. brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude was further purified using silica gel column chromatography purification eluting with MeOH / CH2Cl2 gradients (0- 5%) to afford tert-butyl {3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- oxopropyl}carbamate as a colorless oil (700.1 mg, 98.2% yield).

[0248] 1H NMR (600 MHz, CDCl3) δ 4.30 – 4.03 (m, 3H), 3.83 – 3.74 (m, 1H), 3.63 – 3.57 (m, 1H), 3.46 – 3.39 (m, 1H), 2.57 – 2.48 (m, 1H), 2.01 – 1.91 (m, 1H), 1.43 (s, 3H) ppm.

[0249] MS: mass calcd for C15H24N2O4: 296.2, found: m / z = 197.0 [M-Boc+H]+Step 2: Synthesis of 3-amino-1-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]propan-1-one.

[0250] In a 100 mL RBF, tert-butyl {3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-3-oxopropyl}carbamate (210.0 mg, 0.7 mmol) was dissolved in CH2Cl2 (10 mL), then TFA (0.5 mL) was added dropwise under N2atmosphere. The reaction mixture was allowed to stir at rt for 2 hours, while being monitored with TLC. Once the reaction was completed, the mixture was quenched with 2M NaOH (aq., 40 mL) and extracted with CH2Cl2 (5 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford the 3-amino-1-[7,8- didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]propan-1-one (129.5 mg, 92.8% yield).

[0251] 1H NMR (600 MHz, CD3OD) δ 4.29 (t, J = 2.5 Hz, 1H), 4.19 (t, J = 2.5 Hz, 1H), 4.14 (dt, J = 6.7, 2.5 Hz, 2H), 3.84 – 3.81 (m, 1H), 3.80 – 3.75 (m, 1H), 3.69 – 3.66 (m, 1H), 3.65 – 3.61 (m, 1H), 3.24 – 3.18 (m, 2H), 2.86 – 2.79 (m, 2H), 2.04 – 1.99 (m, 1H), 1.97 – 1.92 (m, 1H) ppm.

[0252] MS: mass calcd for C10H16N2O2: 196.1, found: m / z = 197.0 [M+H]+. Example 19: Synthesis of 37-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-37-4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1-oic acid.

[0253] 7,8-Didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (23.0 mg, 0.2 mmol) was dissolved in DMF (20 mL) in a single-necked flask. To this were added DIEA (24 mg, 3.9 mmolq), 4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontanedioic acid (199.3 mg, 0.3 mmol), HOBt monohydrate (37.2 mg, 0.3 mmol), and EDCI (53.6 mg, 0.3 mmol). The mixture was stirred at rt for 16 h, and the mixture was concentrated under reduced pressure and purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min). Desired fractions were collected and freeze-dried to afford 37-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-37-oxo- 4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1-oic acid as a yellow oil (70.0 mg, 53.7% yield).

[0254] LC-MS: mass calcd for C33H59NO15: 709.39, found: m / z = 710.86 [M+H]+.

[0255] 1H NMR (400 MHz, CDCl3) δ 4.28 (s, 1H), 4.12 (s, 3H), 3.84 – 3.76 (m, 6H), 3.76 – 3.57 (m, 42H), 2.68 – 2.56 (m, 4H), 2.02 – 1.92 (m, 2H) ppm. Example 20: Synthesis of tert-butyl (4S)-4-amino-5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-5-oxopentanoate.Step 1: Synthesis of tert-butyl (4S)-5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxopentanoate.

[0256] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5- oxopentanoic acid (612.5 mg, 1.4 mmol) was dissolved in DMF (6 mL) in a single-neck flask. To this solution DIEA (310.2 mg, 2.4 mmol) and HATU (912.4 mg, 2.4 mmol) were added. The mixture was stirred at rt for 1 h, and 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (150.2 mg, 1.2 mmol) was added. The reaction was monitored by LC-MS until the complete consumption of starting materials. The mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography purification eluting with 100% CH2Cl2to afford tert-butyl (4S)-5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]- 4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxopentanoate as a yellow oil (500.2 mg, 78.3% yield).

[0257] LC-MS: mass calcd for C31H36N2O6: 532.26, found: m / z = 533.05 [M+H]+. Step 2: Synthesis of tert-butyl (4S)-4-amino-5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-5-oxopentanoate.

[0258] tert-Butyl (4S)-5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxopentanoate (500.0 mg, 0.9 mmol) was dissolved in DMF (5 mL) in a single-neck flask. Piperidine (2.0 mL) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford tert-butyl (4S)-4- amino-5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-5-oxopentanoate as a yellow oil (220.9 mg, 75.7% yield).

[0259] LC-MS: mass calcd for C16H26N2O4: 310.19, found: m / z = 311.05 [M+H]+.

[0260] 1H NMR (400 MHz, D2O) δ 4.50 – 4.36 (m, 1H), 4.34 – 4.29 (m, 1H), 4.27 – 4.22 (m, 2H), 4.22 – 4.11 (m, 1H), 3.94 – 3.80 (m, 2H), 3.78 – 3.69 (m, 1H), 3.62 – 3.53 (m, 1H), 2.56 – 2.41 (m, 2H), 2.19 – 1.93 (m, 4H), 1.50 – 1.46 (m, 9H) ppm. Example 21: Synthesis of (3S)-3-amino-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate hydrochloride.Step 1: Synthesis of (3S)-3-[(tert-butoxycarbonyl)amino]-4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.

[0261] To a solution of (S)-3-((tert-butoxycarbonyl)amino)-3-carboxypropyl (2- (trimethylammonio)ethyl) phosphate (1.6 g, 4.1 mmol) in DMF (16 mL), DIEA (1.5 g, 11.2mmol), 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (470.0 mg, 3.8 mmol), HOBt monohydrate (1.2 g, 7.5 mmol) and EDCI (1.4 g, 7.5 mmol) were added sequentially at rt, and the mixture was stirred at rt overnight. LC-MS monitoring indicated completion of the reaction. The mixture was concentrated under reduced pressure. The crude reaction mixture was purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–50% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford (3S)-3-[(tert-butoxycarbonyl)amino]-4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate as a white solid (1.3 g, 70.4% yield).

[0262] LC / MS: mass calcd for C21H38N3O8P: 491.24, found: m / z = 492.35 [M+H]+.

[0263] 1H NMR (400 MHz, CD3OD) δ 4.70 – 4.60 (m, 1H), 4.44 – 4.25 (m, 4H), 4.24 – 4.04 (m, 3H), 3.99 (q, J = 6.5 Hz, 2H), 3.90 – 3.73 (m, 3H), 3.70 – 3.59 (m, 3H), 3.25 (s, 9H), 2.22 – 1.85 (m, 4H), 1.46 (d, J = 3.9 Hz, 9H) ppm. Step 2: Synthesis of (3S)-3-amino-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate hydrochloride.

[0264] To a solution of (3S)-3-[(tert-butoxycarbonyl)amino]-4-[7,8-didehydro- 3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate (400.0 mg, 0.8 mmol) in MeOH (4 mL) was added HCl (4 mL, 8.0 mmol, 2.0 N in methanol) at 0 °C. The mixture was stirred at rt for 2 h. Reaction progress was monitored by LC-MS, after which the mixture was concentrated under reduced pressure and lyophilized to afford (3S)-3-amino-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutyl 2- (trimethylazaniumyl)ethyl phosphate hydrochloride as a yellow solid (317.1 mg, 91.2% yield).

[0265] LC / MS: mass calcd for C16H30N3O6P: 391.19, found: m / z = 392.27 [M+H]+. Example 22: Synthesis of 2,5-dioxopyrrolidin-1-yl 37-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-37-oxo-4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1-Schemeoxazonin-5(2H)-yl]-37-oxo-4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1- oate.

[0266] 37-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-37-oxo- 4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1-oic acid (65.0 mg, 0.1 mmol) was dissolved in CH2Cl2 (2 mL) in a single-necked flask. At 0 °C (ice–water bath), DIEA (24.0 mg, 0.2 mmol) and DSC (23.0 mg, 0.1 mmol) were added. The mixture was stirred at rt for 1 h, and reaction completion was confirmed by LC-MS. The mixture was concentrated under reduced pressure and purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min). Desired fractions were collected and freeze-dried to afford 2,5-dioxopyrrolidin-1-yl 37-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-37-oxo-4,7,10,13,16,19,22,25,28,31,34- undecaoxaheptatriacontan-1-oate as a colorless oil (36.4 mg, 45.2% yield).

[0267] LC-MS: mass calcd for C37H62N2O17: 806.40, found: m / z = 807.66 [M+H]+.

[0268] 1H NMR (400 MHz, CDCl3) δ 4.31–4.26 (m, 1H), 4.17–4.10 (m, 3H), 3.89– 3.76 (m, 6H), 3.71–3.60 (m, 42H), 2.90 (t, J = 6.5 Hz, 2H), 2.84 (s, 4H), 2.64 (t, J = 6.5 Hz, 2H), 2.02–1.92 (m, 2H) ppm. Example 23: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-(4- hydroxy-3,3-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pentyl)-4-oxobutanamide.Scheme:

[0269] To a 100 mL RBF was added LDA (18.0 mL, 18.0 mmol, 1.0 M in THF) at -78 °C, followed by the slow addition of methyl isobutyrate (1.5 g, 15.0 mmol). The mixture was stirred at -78 °C for 20 min and 1-bromo-2-chloroethane (2.4 g, 16.5 mmol) was added. The mixture was slowly warmed to rt and stirred for 16 h. The reaction mixture was slowly quenched at 0 °C (ice bath) with 1M HCl (aq., 50 mL) and extracted with EA (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (0-5%) to afford methyl 4-chloro- 2,2-dimethylbutanoate as a light-yellow liquid (1.0 g, 41.2% yield).

[0270] 1H NMR (600 MHz, CDCl3) δ 3.68 (s, 3H), 3.52 – 3.46 (m, 2H), 2.08 – 2.02 (m, 2H), 1.22 (s, 6H) ppm. Step 2: Synthesis of methyl 4-azido-2,2-dimethylbutanoate.

[0271] To a 75 mL sealed tube were added methyl 4-chloro-2,2-dimethylbutanoate (1.0 g, 6.1 mmol), sodium azide (520.0 mg, 8.0 mmol) and DMSO (15 mL). The mixture was stirred at 70 °C for 16 h. The mixture was cooled to rt and diluted with EA (100 mL) andwashed with water (3 x 50 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated by rotary evaporation under reduced pressure and the residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (0-5%) to afford methyl 4-azido-2,2-dimethylbutanoate as a light-yellow liquid (875.0 mg, 84.3% yield).

[0272] 1H NMR (600 MHz, CDCl3) δ 3.68 (s, 3H), 3.29 – 3.23 (m, 2H), 1.88 – 1.81 (m, 2H), 1.21 (s, 6H) ppm. Step 3: Synthesis of 5-azido-3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)sulfonyl)pentan-2- one.

[0273] To a 50 mL RBF was added 1-(methylsulfonyl)-4-(trifluoromethyl)benzene (673.0 mg, 3.0 mmol) in THF (8 mL) at -78 °C followed by the slow addition of LDA (3.0 mL, 6.0 mmol, 2.0 M in THF). The mixture was stirred at -78 °C for 20 min and 4-azido-2,2- dimethylbutanoate (514.0 mg, 3.0 mmol) in THF (2 mL) was added. The mixture was stirred at -78 °C for 1 h and rt for 15 h. The mixture was slowly quenched at 0 °C (ice bath) with 1M HCl (aq., 20 mL) and extracted with EA (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (5-30%) to afford a mixture of 5-azido-3,3-dimethyl-1-((4- (trifluoromethyl)phenyl)sulfonyl)pentan-2-one (76 wt%) and 1-(methylsulfonyl)-4- (trifluoromethyl)benzene (24 wt%) as a yellow liquid (605.2 mg).

[0274] 1H NMR (600 MHz, CDCl3) δ 8.13 – 8.08 (m, 2H), 7.88 – 7.82 (m, 2H), 4.42 (s, 2H), 3.26 (t, J = 6.9 Hz, 2H), 1.79 (t, J = 6.9 Hz, 2H), 1.18 (s, 6H) ppm.

[0275] 19F NMR (565 MHz, CDCl3) δ -63.25 (s, 3F) ppm. Step 4: Synthesis of 5-azido-3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)sulfonyl)pentan-2-ol.

[0276] To a 100 mL RBF was added 5-azido-3,3-dimethyl-1-((4- (trifluoromethyl)phenyl)sulfonyl)pentan-2-one (76 wt% mixture, 304.0 mg, 0.8 mmol) in MeOH (10 mL) at 0 °C (ice bath) followed by the addition of NaBH4(60.0 mg, 1.6 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was quenched with water (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (5- 30%) to afford a mixture of 5-azido-3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)sulfonyl)pentan-2-ol (76 wt%) and 1-(methylsulfonyl)-4- (trifluoromethyl)benzene (24 wt%) as a colorless liquid (292.0 mg).

[0277] 1H NMR (600 MHz, CDCl3) δ 8.12 – 8.06 (m, 2H), 7.90 – 7.84 (m, 2H), 3.95 (d, J = 9.8 Hz, 1H), 3.39 – 3.34 (m, 1H), 3.33 – 3.29 (m, 1H), 3.29 – 3.24 (m, 1H), 3.23 – 3.16 (m, 2H), 1.75 – 1.67 (m, 1H), 1.49 – 1.41 (m, 1H), 0.89 (d, J = 7.6 Hz, 6H) ppm.

[0278] 19F NMR (565 MHz, CDCl3) δ -63.23 (s, 3F) ppm. Step 5: Synthesis of 5-amino-3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)sulfonyl)pentan-2-ol.

[0279] To a 100 mL RBF were added 5-azido-3,3-dimethyl-1-((4- (trifluoromethyl)phenyl)sulfonyl)pentan-2-ol (76 wt% mixture, 292.0 mg, 0.6 mmol), dry Pd / C (10 wt%, 50 mg) and MeOH (5 mL). The mixture was degassed under vacuum and filled with H2. The mixture was stirred at r.t. under H2 (1 atm) for 1 h. The mixture was filtered through a pad of Celite and concentrated by rotary evaporation under reduced pressure to afford a crude mixture of 5-amino-3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)sulfonyl)pentan-2-ol (72 wt%) and 1-(methylsulfonyl)-4-(trifluoromethyl)benzene (28 wt%) as a colorless liquid (271.0 mg).

[0280] 1H NMR (600 MHz, CDCl3) δ 8.12 – 8.06 (m, 2H), 7.81 – 7.76 (m, 2H), 3.93 (dd, J = 7.9, 3.7 Hz, 1H), 3.34 – 3.26 (m, 2H), 2.81 – 2.71 (m, 2H), 1.53 – 1.44 (m, 1H), 1.37 – 1.29 (m, 1H), 0.91 (s, 3H), 0.84 (s, 3H) ppm.

[0281] 19F NMR (565 MHz, CDCl3) δ -63.12 (s, 3F) ppm. Step 6. Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-(4- hydroxy-3,3-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pentyl)-4-oxobutanamide.

[0282] To a 100 mL RBF were added 5-amino-3,3-dimethyl-1-((4- (trifluoromethyl)phenyl)sulfonyl)pentan-2-ol (72 wt% mixture, 271.0 mg, 0.57 mmol), 2,5- dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoate (184.0 mg, 0.57 mmol), DIEA (700 µL, 4.0 mmol) and CH2Cl2 (10 mL). The mixture was stirred at rt for 1 h. The mixture was concentrated by rotary evaporation under reduced pressure and the residue was subjected to silica gel column chromatography purification eluting with MeOH / CH2Cl2 gradients (0-6%) to afford 4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-N-(4-hydroxy-3,3-dimethyl-5-{[4- (trifluoromethyl)phenyl]sulfonyl}pentyl)-4-oxobutanamide (154.0 mg, 50.1% yield over 4 steps) as a white solid.

[0283] 1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 6.36 – 6.19 (m, 1H), 4.25 (t, J = 2.5 Hz, 1H), 4.15 – 4.09 (m, 3H), 4.08 – 4.02 (m, 1H), 3.85 – 3.73 (m, 3H), 3.67 – 3.56 (m, 2H), 3.31 – 3.20 (m, 3H), 3.18 – 3.08 (m, 1H), 2.70 – 2.63 (m, 2H), 2.53 – 2.45 (m, 2H), 2.02 – 1.91 (m, 2H), 1.63 – 1.54 (m, 1H), 1.41 – 1.32 (m, 1H), 0.85 (dd, J = 16.1, 3.0 Hz, 6H) ppm.

[0284] 19F NMR (565 MHz, CDCl3) δ -63.16 (s, 3F) ppm. Example 24: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-[4- hydroxy-3,3-dimethyl-5-(methylsulfonyl)pentyl]-4-oxobutanamide.Step 1: Synthesis of methyl 4-chloro-2,2-dimethylbutanoate.

[0285] To a 100 mL RBF was added LDA (18.0 mL, 18.0 mmol, 1.0 M in THF) at -78 °C, followed by the slow addition of methyl isobutyrate (1.5 g, 15.0 mmol). The mixture was stirred at -78 °C for 20 min and 1-bromo-2-chloroethane (2.4 g, 16.5 mmol) was added. The mixture was slowly warmed to rt and stirred for 16 h. The reaction mixture was slowlyquenched at 0 °C (ice bath) with 1M HCl (aq., 50 mL) and extracted with EA (3 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (0-5%) to afford methyl 4-chloro- 2,2-dimethylbutanoate as a light-yellow liquid (1.0 g, 41.2% yield).

[0286] 1H NMR (600 MHz, CDCl3) δ 3.68 (s, 3H), 3.52 – 3.46 (m, 2H), 2.08 – 2.02 (m, 2H), 1.22 (s, 6H) ppm. Step 2: Synthesis of methyl 4-azido-2,2-dimethylbutanoate.

[0287] To a 75 mL sealed tube were added methyl 4-chloro-2,2-dimethylbutanoate (1.0 g, 6.1 mmol), sodium azide (520.0 mg, 8.0 mmol) and DMSO (15 mL). The mixture was stirred at 70 °C for 16 h. The mixture was cooled to rt and diluted with EA (100 mL) and washed with water (3 x 50 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated by rotary evaporation under reduced pressure and the residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (0-5%) to afford methyl 4-azido-2,2-dimethylbutanoate as a light-yellow liquid (875.0 mg, 84.3% yield).

[0288] 1H NMR (600 MHz, CDCl3) δ 3.68 (s, 3H), 3.29 – 3.23 (m, 2H), 1.88 – 1.81 (m, 2H), 1.21 (s, 6H) ppm. Step 3: Synthesis of 5-azido-3,3-dimethyl-1-(methylsulfonyl)pentan-2-one.

[0289] To a 50 mL RBF was added dimethyl sulfone (282.0 mg, 3.0 mmol) in THF (4 mL) at -78 °C followed by the slow addition of LDA (3.0 mL, 6.0 mmol, 2.0 M in THF). The mixture was stirred at -78 °C for 20 min and methyl 4-azido-2,2-dimethylbutanoate (514.0 mg, 3.0 mmol) in THF (2 mL) was added. The mixture was stirred at -78 °C for 1 h and rt for 15 h. The mixture was slowly quenched at 0 °C (ice bath) with 1M HCl (aq., 20 mL) and extracted with EA (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (5-50%) to afford 5-azido-3,3-dimethyl-1-(methylsulfonyl)pentan-2-one as a colorless liquid (229.0 mg, 33.3% yield).

[0290] 1H NMR (600 MHz, CDCl3) δ 4.19 (q, J = 0.9 Hz, 2H), 3.32 (t, J = 7.0 Hz, 2H), 3.14 (t, J = 0.9 Hz, 3H), 1.85 (t, J = 7.0 Hz, 2H), 1.22 (s, 6H) ppm.Step 4: Synthesis of 5-azido-3,3-dimethyl-1-(methylsulfonyl)pentan-2-ol.

[0291] To a 100 mL RBF was added 5-azido-3,3-dimethyl-1- (methylsulfonyl)pentan-2-one (229.0 mg, 1.0 mmol) in MeOH (5 mL) at 0 °C (ice bath) followed by the addition of NaBH4 (76.1 mg, 2.0 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was quenched with water (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford 5-azido-3,3-dimethyl-1-(methylsulfonyl)pentan- 2-ol as a white solid (202.0 mg, 86.2% yield).

[0292] 1H NMR (600 MHz, CDCl3) δ 4.04 – 3.98 (m, 1H), 3.48 – 3.36 (m, 2H), 3.14 – 3.08 (m, 2H), 3.04 (s, 3H), 1.80 – 1.72 (m, 1H), 1.53 – 1.47 (m, 1H), 0.97 (s, 3H), 0.94 (s, 3H) ppm. Step 5: Synthesis of 5-amino-3,3-dimethyl-1-(methylsulfonyl)pentan-2-ol.

[0293] To a 100 mL RBF were added 5-azido-3,3-dimethyl-1- (methylsulfonyl)pentan-2-ol (200.0 mg, 0.8 mmol), dry Pd / C (10 wt%, 20.1 mg) and MeOH (10 mL). The mixture was degassed under vacuum and filled with H2. The mixture was stirred at rt under H2(1 atm) for 1 h. The mixture was filtered through Celite and concentrated by rotary evaporation under reduced pressure to afford 5-amino-3,3-dimethyl-1- (methylsulfonyl)pentan-2-ol as a colorless liquid (178.0 mg, 100% yield).

[0294] 1H NMR (600 MHz, CDCl3) δ 3.89 (dd, J = 10.4, 1.6 Hz, 1H), 3.14 – 2.99 (m, 5H), 2.87 – 2.78 (m, 2H), 1.58 – 1.51 (m, 1H), 1.42 – 1.34 (m, 1H), 0.91 (d, J = 15.7 Hz, 6H) ppm. Step 6: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-[4- hydroxy-3,3-dimethyl-5-(methylsulfonyl)pentyl]-4-oxobutanamide.

[0295] To a 100 mL RBF were added 5-amino-3,3-dimethyl-1- (methylsulfonyl)pentan-2-ol (180.0 mg, 0.9 mmol), 2,5-dioxopyrrolidin-1-yl 4-[7,8- didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoate (277.0 mg, 0.9 mmol), DIEA (454 μL, 2.6 mmol) and CH2Cl2 (5 mL). The mixture was stirred at rt for 1 h. The mixture was concentrated by rotary evaporation under reduced pressure and the residue was subjected to silica gel column chromatography purification eluting with MeOH / CH2Cl2gradients (0-5%) to afford 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-[4-hydroxy-3,3-dimethyl-5-(methylsulfonyl)pentyl]-4-oxobutanamide as a white solid (226.0 mg, 63.4% yield).

[0296] 1H NMR (600 MHz, CDCl3) δ 6.53 (s, 1H), 4.52 – 4.36 (m, 1H), 4.26 (t, J = 2.5 Hz, 1H), 4.18 – 4.08 (m, 4H), 3.82 (t, J = 5.4 Hz, 1H), 3.79 – 3.73 (m, 1H), 3.65 (t, J = 5.8 Hz, 1H), 3.59 (q, J = 5.1 Hz, 1H), 3.37 – 3.29 (m, 1H), 3.19 – 3.08 (m, 2H), 3.07 (s, 3H), 3.05 – 3.00 (m, 1H), 2.73 – 2.62 (m, 2H), 2.56 – 2.44 (m, 2H), 2.03 – 1.90 (m, 2H), 1.71 – 1.63 (m, 1H), 1.44 – 1.36 (m, 1H), 0.89 (dd, J = 14.6, 3.2 Hz, 6H) ppm. Example 25: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-(6- hydroxy-7-{[4-(trifluoromethyl)phenyl]sulfonyl}heptyl)-4-oxobutanamide.Scheme:Step 1: Synthesis of ethyl 6-azidohexanoate.

[0297] Ethyl 6-bromohexanoate (15.0 g, 67.2 mmol) was dissolved in water (300 mL) in a single-neck flask. To this solution was added NaN3(8.7 g, 134.4 mmol). The mixture was heated at 110 °C overnight. After cooling to rt, the reaction mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over Na2SO4, and concentrated by rotary evaporation to afford ethyl 6-azidohexanoate as a colorless oil (12.4 g, 96.4% yield).

[0298] 1H NMR (400 MHz, CDCl3) δ 4.13 (q, J = 7.1 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.70 – 1.59 (m, 4H), 1.47 – 1.36 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H) ppm. Step 2: Synthesis of 7-azido-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-one.

[0299] 1-(Methylsulfonyl)-4-(trifluoromethyl)benzene (908.0 mg, 4.1 mmol) was dissolved in THF (10 mL) in a three-neck flask under N2atmosphere. The solution was cooled to -78 °C using a dry ice / acetone bath, and LDA (2.7 mL, 5.4 mmol, 2.0 M in THF) was addeddropwise. The mixture was stirred at -78 °C for 30 min. A solution of ethyl 6-azidohexanoate (500.2 mg, 2.7 mmol) in THF (10 mL) was then added dropwise to the reaction mixture, which was stirred at -78 °C for 2 h. Reaction progress was monitored by TLC. The mixture was warmed to 0 °C and quenched by the addition of sat. NH4Cl solution (aq., 100 mL). The mixture was extracted with EA (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography purification eluting with EA / PE gradients (0-30%) to afford 7- azido-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-one as a yellow oil (850.3 mg, 86.6% yield).

[0300] 1H NMR (400 MHz, CDCl3) δ 8.22 – 7.99 (m, 2H), 7.96 – 7.73 (m, 2H), 4.21 (s, 2H), 3.29 (t, J = 6.8 Hz, 2H), 2.76 (t, J = 7.1 Hz, 2H), 1.65 – 1.61 (m, 4H), 1.42 – 1.34 (m, 2H) ppm. Step 3: Synthesis of 7-azido-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-ol.

[0301] 7-Azido-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-one (850.0 mg, 2.3 mmol) was dissolved in MeOH (20 mL) in a single-neck flask. The solution was cooled in an ice–water bath, and NaBH4(45.2 mg, 1.2 mmol) was added. The mixture was stirred at rt for 1 h. The reaction was quenched by the addition of water (1 mL) and concentrated under reduced pressure. The residue was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product- containing fractions were combined and lyophilized to afford 7-azido-1-((4- (trifluoromethyl)phenyl)sulfonyl)heptan-2-ol as a colorless oil (470 mg, 56.0% yield).

[0302] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 4.29 – 4.19 (m, 1H), 3.34 – 3.25 (m, 3H), 3.25 – 3.19 (m, 1H), 3.15 (d, J = 2.9 Hz, 1H), 1.67 – 1.56 (m, 4H), 1.52 – 1.38 (m, 4H) ppm. Step 4: Synthesis of 7-amino-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-ol.

[0303] 7-Azido-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-ol (470.0 mg, 1.3 mmol) was dissolved in MeOH (10 mL) in a single-neck flask and purged with N2 (3 cycles). Dry Pd / C (10 wt%, 47.1 mg) was then added. The mixture was degassed under vacuum and filled with H2. The reaction mixture was stirred at rt for 1 h under H2(1 atm). The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford 7-amino-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-ol as a pale-yellow solid (410.3 mg, 93.0% yield).

[0304] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.2 Hz, 2H), 8.01 – 7.79 (m, 2H), 4.25 (s, 1H), 3.38 – 3.16 (m, 2H), 2.73 (t, J = 6.9 Hz, 2H), 1.82 – 1.15 (m, 8H) ppm. Step 5: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-(6- hydroxy-7-{[4-(trifluoromethyl)phenyl]sulfonyl}heptyl)-4-oxobutanamide.

[0305] 7-Amino-1-((4-(trifluoromethyl)phenyl)sulfonyl)heptan-2-ol (280.0 mg, 0.8 mmol) was dissolved in DMF (3 mL) in a single-neck flask and purged with N2 (3–5 cycles). TEA (250 mg, 2.5 mmol) and 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoate (399.3 mg, 1.2 mmol) were added at 0 °C (ice bath). The mixture was stirred at rt for 16 h. The crude reaction mixture was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-(6-hydroxy-7-{[4- (trifluoromethyl)phenyl]sulfonyl}heptyl)-4-oxobutanamide as a white solid (160.2 mg, 36.6% yield).

[0306] 1H NMR (400 MHz, CD3OD) δ 8.16 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 4.28 – 4.21 (m, 2H), 4.20 – 4.06 (m, 3H), 3.87 – 3.69 (m, 3H), 3.62 – 3.57 (m, 1H), 3.44 – 3.39 (m, 2H), 3.20 – 3.12 (m, 2H), 2.74 – 2.65 (m, 2H), 2.56 – 2.44 (m, 2H), 2.12 – 2.01 (m, 1H), 1.98 – 1.88 (m, 1H), 1.62 – 1.30 (m, 8H) ppm.

[0307] 19F NMR (376 MHz, CD3OD) δ -64.65 (s, 3F) ppm. Example 26: Synthesis of N-(4-hydroxy-3,3-dimethyl-5-{[4- (trifluoromethyl)phenyl]sulfonyl}pentyl)-7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonine- 5(2H)-carboxamide.Scheme: Step 1:Synthesis of N-(4-hydroxy-3,3-dimethyl-5-{[4- (trifluoromethyl)phenyl]sulfonyl}pentyl)-7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonine- 5(2H)-carboxamide.

[0308] An RBF with 5-amino-3,3-dimethyl-1-((4- (trifluoromethyl)phenyl)sulfonyl)pentan-2-ol (70.0 mg, 0.6 mmol) was purged with N2 / vacuum cycle 3 times, then dissolved in THF (1.5 mL). The mixture was cooled to 0 °C (ice / water bath), before the addition of pyridine (133.6 mg, 1.7 mmol), triphosgene (498.6 mg, 1.7 mmol). The mixture was stirred at 0 °C for 1 h, then filtered with Celite, and washed with THF (3 mL). The filtrate was concentrated by rotary evaporation under reduced pressure. The resulting crude mixture was dissolved in DMF (1.5 mL), then TEA (170.1 mg, 1.7 mmol), 7,8- didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (190.1 mg, 0.6 mmol) were added. The mixture was stirred at rt for 1 h, while being monitored by LC-MS. Once the reaction was completed, the crude was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford N-(4-hydroxy-3,3-dimethyl-5-{[4- (trifluoromethyl)phenyl]sulfonyl}pentyl)-7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonine- 5(2H)-carboxamide as a white solid (132.1 mg, 48.0% yield).

[0309] LC-MS: mass calcd for C22H29F3N2O5S: 490.17, found: m / z = 491.60 [M+H]+.

[0310] 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 4.63 (s, 1H), 4.17 – 4.11 (m, 4H), 4.11 – 4.09 (m, 1H), 3.85 – 3.78 (m, 2H), 3.51 – 3.43 (m, 2H), 3.34 – 3.20 (m, 3H), 3.18 – 3.10 (m, 1H), 1.87 – 1.77 (m, 2H), 1.60 – 1.57 (m, 1H), 1.45 – 1.33 (m, 1H), 0.86 (d, J = 17.2 Hz, 6H) ppm.Example 27: Synthesis of (3S)-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-oxobutanoyl}amino)-4-{[4-hydroxy-3,3-dimethyl-5-(phenylsulfonyl)pentyl]amino}-4- oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.ep : yn ess of -amno-,- me y--penysufony penan--o.

[0311] A 100 mL RBF with 5-azido-3,3-dimethyl-1-(phenylsulfonyl)pentan-2-ol (1.0 g, 3.4 mmol) was dissolved in CH3OH (50 mL), before the addition of Pd / C (10 wt% dry, 100.1 mg). The mixture was purged with H2 / vacuum cycles 3 times, and then stirred at rt for 0.5 h, while being monitored by TLC. Once the reaction was completed, the crude mixture was filtered with Celite and washed with CH3OH (30 mL). The filtrate was concentrated by rotary evaporation under reduced pressure to afford 5-amino-3,3-dimethyl-1-(phenylsulfonyl)pentan- 2-ol as a yellow oil (550.0 mg, 60% yield).

[0312] LC-MS: mass calcd for C13H21NO3S: 271.12, found: m / z = 272.09 [M+H]+.

[0313] 1H NMR (400 MHz, CD3OD) δ 7.98 (d, J = 7.8 Hz, 2H), 7.73 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.7 Hz, 2H), 3.77 (d, J = 9.2 Hz, 1H), 3.41 (d, J = 14.5 Hz, 1H), 3.30 (d, J = 5.3 Hz, 1H), 2.69 – 2.56 (m, 2H), 1.51 (m, 1H), 1.37 – 1.28 (m, 1H), 0.85 (s, 6H) ppm. Step 2: Synthesis of (3S)-3-((tert-butoxycarbonyl)amino)-4-((4-hydroxy-3,3-dimethyl-5- (phenylsulfonyl)pentyl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate.

[0314] To a 50 mL RBF were added 5-amino-3,3-dimethyl-1- (phenylsulfonyl)pentan-2-ol (200.0 mg, 0.7 mmol), DIEA (381.3 mg, 2.9 mmol), HOBt monohydrate (149.2 mg, 1.1 mmol), (S)-3-((tert-butoxycarbonyl)amino)-3-carboxypropyl (2- (trimethylammonio)ethyl) phosphate (312.0 mg, 0.8 mmol) and DMF (5 mL). The mixture was purged with N2 / vacuum cycle 3 times, before the addition of EDCI (212.2 mg, 1.1 mmol). The reaction was stirred at rt for 16 h. The mixture was concentrated by rotary evaporation under reduced pressure and purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product- containing fractions were combined and lyophilized to afford (3S)-3-((tert- butoxycarbonyl)amino)-4-((4-hydroxy-3,3-dimethyl-5-(phenylsulfonyl)pentyl)amino)-4- oxobutyl (2-(trimethylammonio)ethyl) phosphate as a white solid (160.3 mg, 31.0% yield).

[0315] LC-MS: mass calcd for C27H48N3O10PS: 637.28, found: mz = 638.36 [M+H]+. Step 3: Synthesis of (3S)-3-amino-4-((4-hydroxy-3,3-dimethyl-5- (phenylsulfonyl)pentyl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate.

[0316] To a 50 mL RBF were added (3S)-3-((tert-butoxycarbonyl)amino)-4-((4- hydroxy-3,3-dimethyl-5-(phenylsulfonyl)pentyl)amino)-4-oxobutyl (2- (trimethylammonio)ethyl) phosphate (80.0 mg, 0.1 mmol), CH2Cl2 (3 mL), and TFA (0.6 mL). The reaction was stirred at rt for 1 h. The mixture was concentrated by rotary evaporation under reduced pressure to afford (3S)-3-amino-4-((4-hydroxy-3,3-dimethyl-5- (phenylsulfonyl)pentyl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate as a colorless oil (67.1 mg, 99.0% yield).

[0317] LC-MS: mass calcd for C22H40N3O8PS: 537.23, found: m / z = 538.21 [M+H]+.Step 4: Synthesis of (3S)-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-4-{[4-hydroxy-3,3-dimethyl-5-(phenylsulfonyl)pentyl]amino}-4- oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.

[0318] To a 50 mL RBF were added (3S)-3-amino-4-((4-hydroxy-3,3-dimethyl-5- (phenylsulfonyl)pentyl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate (67.1 mg, 0.1 mmol), 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-oxobutanoate (44.0 mg, 0.1 mmol), TEA (25.0 mg, 0.2 mmol), CH2Cl2(5 mL). The reaction was stirred at rt for 2 h. The mixture was concentrated by rotary evaporation under reduced pressure and purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford (3S)-3-({4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-4-{[4-hydroxy-3,3-dimethyl-5- (phenylsulfonyl)pentyl]amino}-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate as a white solid (34.0 mg, 36.9% yield).

[0319] LC-MS: mass calcd for C33H53N4O11PS: 744.32, found: m / z = 745.30 [M+H]+.

[0320] 1H NMR (400 MHz, CD3OD) δ 7.98 (d, J = 7.8 Hz, 2H), 7.74 (t, J = 7.3 Hz, 1H), 7.65 (t, J = 7.6 Hz, 2H), 4.61 (s, 3H), 4.50 – 4.40 (m, 1H), 4.30 (s, 3H), 4.26 – 4.21 (m, 1H), 4.18 – 4.13 (m, 1H), 4.07 – 3.90 (m, 2H), 3.87 – 3.76 (m, 2H), 3.73 – 3.64 (m, 3H), 3.63 – 3.56 (m, 1H), 3.47 – 3.40 (m, 1H), 3.31 – 3.27 (m, 1H), 3.25 (s, 9H), 3.23 – 3.07 (m, 2H), 2.88 – 2.69 (m, 1H), 2.68 – 2.57 (m, 1H), 2.56 – 2.43 (m, 1H), 2.31 – 2.12 (m, 1H), 2.05 (p, J = 5.2 Hz, 1H), 2.00 – 1.84 (m, 2H), 1.61 – 1.47 (m, 1H), 1.45 – 1.30 (m, 1H), 0.86 (s, 6H) ppm.

[0321] 31P NMR (162 MHz, CD3OD) δ -0.16 – -1.05 (m, 1P). Example 28: Synthesis of 5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-3,3-dimethyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pentan-2-yl carbonochloridate.oxobutanoyl}amino)-3,3-dimethyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pentan-2-yl carbonochloridate.

[0322] A 100 mL RBF with 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-N-(4-hydroxy-3,3-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pentyl)-4- oxobutanamide (136.0 mg, 0.3 mmol) was purged with N2 / vacuum cycle 3 times, before the addition of triphosgene (231.2 mg, 0.8 mmol) and THF (12 mL). The mixture was stirred at 0 °C for 5 min, then pyridine (74 μL, 0.9 mmol) was added dropwise. The mixture was stirred at 0 °C for 10 min, then slowly warmed to rt for 30 min. The mixture was filtered and washed with THF (3 mL x 3). The resulting filtrate was concentrated by rotary evaporation under reduced pressure to give 5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-3,3-dimethyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pentan-2-yl carbonochloridate as a colorless oil (165.8 mg, 109.3% yield). The crude must be used immediately for the next step, so no characterization was performed. Example 29: Synthesis of 5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-3,3-dimethyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pentan-2-yl 2,5- dioxopyrrolidin-1-yl carbonate.4- oxobutanoyl}amino)-3,3-dimethyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pentan-2-yl 2,5- dioxopyrrolidin-1-yl carbonate.

[0323] To a RBF was added 5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-3,3-dimethyl-1-{[4- (trifluoromethyl)phenyl]sulfonyl}pentan-2-yl carbonochloridate (165.8 mg, 0.3 mmol) and N- Hydroxysuccinimide (180.0 mg, 1.5 mmol), and the flask was purged with N2 / vacuum cycle 3 times, before the addition of THF (11 mL) at 0 °C. Then dry pyridine (74 μL, 0.9 mmol) was added dropwise. The mixture was stirred at 0 °C for 10 min, then slowly warmed to room temperature for 2 h. The mixture was filtered and washed with THF (3 mL x 3). The resulting filtrate was concentrated by rotary evaporation under reduced pressure. The crude mixture was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford 5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-3,3-dimethyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pentan-2-yl 2,5- dioxopyrrolidin-1-yl carbonate as a white solid (51.0 mg, 29.8% yield).

[0324] MS: mass calcd for C30H36F3N3O10S: 687.2, found: m / z = 688.2 [M+H]+

[0325] 1H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 6.15 – 6.07 (m, 1H), 5.25 – 5.20 (m, 1H), 4.29 – 4.07 (m, 4H), 3.85 – 3.74 (m, 2H), 3.70 – 3.59 (m, 2H), 3.59 – 3.54 (m, 1H), 3.51 – 3.45 (m, 1H), 3.33 – 3.23 (m, 1H), 3.16 – 3.07 (m, 1H), 2.85 (s, 4H), 2.72 – 2.60 (m, 2H), 2.57 – 2.45 (m, 2H), 2.03 – 1.92 (m, 2H), 1.52 – 1.43 (m, 2H), 0.95 (s, 6H) ppm. Example 30: Synthesis of 7-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}heptan-2-yl 2,5- dioxopyrrolidin-1-yl carbonate.Step 1: Synthesis of 7-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}heptan-2-yl 2,5-dioxopyrrolidin- 1-yl carbonate.

[0326] 4-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-(6- hydroxy-7-{[4-(trifluoromethyl)phenyl]sulfonyl}heptyl)-4-oxobutanamide (100.3 mg, 0.2 mmol) was dissolved in THF (5 mL) in a single-neck flask and purged with N2 (3 cycles). Pyridine (45.6 mg, 0.5 mmol) was added at 0 °C (ice bath) and the mixture was stirred for 5 min. Triphosgene (136.9 mg, 0.46 mmol) was then added, and the reaction was stirred at 0 °C for 1 h. The mixture was filtered through Celite, washed with THF (20 mL), and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (5 mL), purged with N2(3 cycles), and cooled to 0 °C (ice bath). Pyridine (45.5 mg, 0.6 mmol) was added and stirred for 5 min, followed by the addition of N-hydroxysuccinimide (64.2 mg, 0.6 mmol). The reaction was stirred at 0 °C for 30 min and monitored by LC-MS until complete consumption of the starting material. The mixture was concentrated under reduced pressure and the residue was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford 7-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}heptan-2-yl 2,5- dioxopyrrolidin-1-yl carbonate as a white solid (25.0 mg, 20.2% yield).

[0327] LC-MS: mass calcd for C30H36F3N3O10S: 687.21, found: m / z = 688.20 [M+H]+.

[0328] 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 6.09 – 5.96 (m, 1H), 5.36 – 5.28 (m, 1H), 4.26 (t, J = 2.6 Hz, 1H), 4.15 – 4.08 (m, 3H), 3.86 – 3.73 (m, 2H), 3.69 – 3.55 (m, 3H), 3.40 (dd, J = 15.2, 3.5 Hz, 1H), 3.27 – 3.15 (m, 2H), 2.85 (s, 4H), 2.71 – 2.63 (m, 2H), 2.54 – 2.46 (m, 2H), 2.02 – 1.91 (m, 2H), 1.85 – 1.76 (m, 2H), 1.52 – 1.46 (m, 2H), 1.41 – 1.30 (m, 4H) ppm.

[0329] 19F NMR (376 MHz, CDCl3) δ -63.25 (s, 3F) ppm. Example 31: Synthesis of 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8- didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)hexanoic acid.Step 1: Synthesis of Methyl N6-((benzyloxy)carbonyl)-N ,N -bis(2-((tert- butyldimethylsilyl)oxy)ethyl)lysinate.

[0330] Methyl N6-((benzyloxy)carbonyl)lysinate (2.0 g, 6.8 mmol) was dissolved in DMF (40 mL) in a single-necked flask. 2-((tert-Butyldimethylsilyl)oxy)acetaldehyde (5.9 g, 34.0 mmol) was added, the mixture was cooled to 0 °C, and NaBH(OAc)3(7.2 g, 34.0 mmol) was added slowly. The reaction was stirred at rt overnight. The mixture was cooled to 0 °C andquenched with sat. NaHCO3 (40 mL). The aqueous layer was extracted with EA (3 × 40 mL), and the combined organic layers were washed with LiCl (aq, 5% wt) (3 × 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE = 1:80) to afford N6-((benzyloxy)carbonyl)-N2,N2-bis(2-((tert- butyldimethylsilyl)oxy)ethyl)lysinate as a yellow oil (2.0 g, 48.2% yield).

[0331] 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.32 (m, 5H), 5.12 (s, 2H), 4.77 (s, 1H), 3.74 – 3.70 (m, 1H), 3.69 (s, 3H), 3.59 (t, J = 6.8 Hz, 4H), 3.41 – 3.35 (m, 1H), 3.21 (q, J = 6.5 Hz, 2H), 2.83 – 2.71 (m, 4H), 1.79 – 1.69 (m, 1H), 1.56 – 1.51 (m, 2H), 1.38 – 1.30 (m, 1H), 0.90 (s, 18H), 0.06 (s, 12H) ppm. Step 2: Synthesis of methyl bis(2-((tert-butyldimethylsilyl)oxy)ethyl)lysinate.

[0332] N6-((Benzyloxy)carbonyl)-N2,N2-bis(2-((tert- butyldimethylsilyl)oxy)ethyl)lysinate (680.0 mg, 1.2 mmol) was dissolved in CH3OH (20 mL) in a single-necked flask, purged with N2three times, and Pd / C (62.1 mg, 58.3 µmol, 10 wt%, dry) was added. The suspension was purged with H2 three times and stirred at rt overnight under H2 (1 atm) atmosphere. The mixture was filtered through Celite, the solids were rinsed with CH3OH (10 mL), and the filtrate was concentrated under reduced pressure to afford methyl bis(2-((tert-butyldimethylsilyl)oxy)ethyl)lysinate as a colorless oil (430 mg, 77.3% yield).

[0333] LC-MS: mass calcd for C23H52N2O4Si2: 476.35, found: m / z = 477.40 [M+H]+.

[0334] 1H NMR (400 MHz, CD3OD) δ 3.70 (s, 4H), 3.64 (t, J = 6.4 Hz, 4H), 3.47 (d, J = 8.0 Hz, 1H), 2.85 – 2.62 (m, 2H), 2.77 – 2.69 (m, 2H), 2.64 (t, J = 7.0 Hz, 1H), 1.79 – 1.69 (m, 1H), 1.67 – 1.58 (m, 1H), 1.52 (s, 3H), 1.42 – 1.31 (m, 1H), 0.93 (s, 18H), 0.09 (s, 12H) ppm. Step 3: Synthesis of methyl 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8- didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)hexanoate.

[0335] Methyl bis(2-((tert-butyldimethylsilyl)oxy)ethyl)lysinate (430.0 mg, 0.9 mmol) was dissolved in CH2Cl2 (8 mL) in a single-necked flask. TEA (273.8 mg, 2.7 mmol) and 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoate (319.7 mg, 1.0 mmol) were added, and the mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and purified using preparativeRP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min). Lyophilization afforded methyl 2-[bis(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)hexanoate as a yellow oil (170.6 mg, 27.7% yield).

[0336] LC-MS: mass calcd for C34H65N3O7Si2: 683.44, found: m / z = 684.60 [M+H]+.

[0337] 1H NMR (400 MHz, CDCl3) δ 5.97 – 5.85 (m, 1H), 4.27 (s, 1H), 4.12 (s, 2H), 3.85 – 3.75 (m, 2H), 3.67 (s, 3H), 3.62 – 3.48 (m, 5H), 3.35 (t, J = 7.4 Hz, 1H), 3.21 (q, J = 6.6 Hz, 2H), 2.82 – 2.60 (m, 6H), 2.56 – 2.45 (m, 2H), 2.03 – 1.91 (m, 2H), 1.77 – 1.68 (m, 1H), 1.60 – 1.37 (m, 6H), 1.33 – 1.27 (m, 1H), 0.88 (s, 18H), 0.04 (s, 12H) ppm. Step 4: Synthesis of 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8- didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)hexanoic acid.

[0338] LiOH monohydrate (250.0 mg) was dissolved in water (5 mL) to give a 5 wt% aqueous LiOH solution. Methyl 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-6- ({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)hexanoate (470.0 mg, 0.7 mmol) was dissolved in MeOH (5 mL) and THF (5 mL) in a single-necked flask. The 5 wt% LiOH(aq) prepared above (5 mL, ca.6.0 mmol) was added, and the mixture was stirred at rt for 1 h. The reaction mixture was adjusted to pH 4–5 with 1 M HCl, extracted with EA (3 × 10 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EA / PE (1:2) to afford 2-[bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-6- ({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)hexanoic acid as a yellow oil (150.4 mg, 32.7% yield).

[0339] LC-MS: mass calcd for C33H63N3O7Si2: 669.42, found: m / z = 668.35 [M- H]-.

[0340] 1H NMR (400 MHz, CD3OD) δ 4.29 – 4.22 (m, 2H), 4.19 – 4.13 (m, 2H), 4.00 (t, J = 4.8 Hz, 4H), 3.90 – 3.69 (m, 5H), 3.64 – 3.58 (m, 1H), 3.49 – 3.41 (m, 2H), 3.27 – 3.18 (m, 2H), 2.74 – 2.67 (m, 2H), 2.56 – 2.48 (m, 2H), 2.07 – 2.02 (m, 1H), 1.99 – 1.90 (m, 2H), 1.88 – 1.79 (m, 1H), 1.78 – 1.68 (m, 1H), 1.63 – 1.50 (m, 3H), 0.96 (s, 18H), 0.16 (s, 12H) ppm.Example 32: Synthesis of 2,5-dioxopyrrolidin-1-yl 2-[bis(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)hexanoate.Oy , y y tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-oxobutanoyl}amino)hexanoate.

[0341] 2-[Bis(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8- didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)hexanoic acid (30.0 mg, 44.8 µmol) was dissolved in CH2Cl2(2 mL) in a single-necked flask. Using an ice– water bath (0 °C), DIEA (8.7 mg, 67.2 µmmol) and DSC (17.2 mg, 67.2 µmmol) were added. The mixture was stirred at rt for 1 h, concentrated under reduced pressure, and purified by preparative TLC on silica gel (EA / PE = 1:2) to afford 2,5-dioxopyrrolidin-1-yl 2-[bis(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-6-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)hexanoate (15.1 mg, 44.0% yield) as a colorless oil.

[0342] LC-MS: mass calcd for C37H68N4O8Si2: 766.44, found: m / z = 767.46 [M+H]+.Example 33: Synthesis of 2,5-dioxopyrrolidin-1-yl 37-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-37-oxo-4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1- oate.oxazonin-5(2H)-yl]-37-oxo-4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1- oate.

[0343] 37-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-37-oxo- 4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontan-1-oic acid (65.0 mg, 0.1 mmol) was dissolved in CH2Cl2(2 mL) in a single-necked flask. At 0 °C (ice–water bath), DIEA (24.0 mg, 0.2 mmol) and DSC (23.0 mg, 0.1 mmol) were added. The mixture was stirred at rt for 1 h, and reaction completion was confirmed by LC-MS. The mixture was concentrated under reduced pressure and purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min). Desired fractions were collected and freeze-dried to afford 2,5-dioxopyrrolidin-1-yl 37-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-37-oxo-4,7,10,13,16,19,22,25,28,31,34- undecaoxaheptatriacontan-1-oate as a colorless oil (36.4 mg, 45.2% yield).

[0344] LC-MS: mass calcd for C37H62N2O17: 806.40, found: m / z = 807.66 [M+H]+.

[0345] 1H NMR (400 MHz, CDCl3) δ 4.31–4.26 (m, 1H), 4.17–4.10 (m, 3H), 3.89– 3.76 (m, 6H), 3.71–3.60 (m, 42H), 2.90 (t, J = 6.5 Hz, 2H), 2.84 (s, 4H), 2.64 (t, J = 6.5 Hz, 2H), 2.02–1.92 (m, 2H) ppm.Example 34: Synthesis of N-{(4S)-4-{[(2S)-2-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-3-methylbutanoyl]amino}-5-[4- (hydroxymethyl)anilino]-5-oxopentyl}urea.onin- 5(2H)-yl]-4-oxobutanoyl}amino)-3-methylbutanoyl]amino}-5-[4-(hydroxymethyl)anilino]-5- oxopentyl}urea.

[0346] (S)-2-((S)-2-Amino-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)- 5-ureidopentanamide (200.2 mg, 0.5 mmol) was dissolved in DMF (4 mL) in a single-neck flask. TEA (160.0 mg, 1.6 mmol) was added, and the mixture was purged with N₂ (3–5 cycles). The solution was cooled in an ice bath to 0 °C, and a solution of 2,5-dioxopyrrolidin-1-yl 4- [7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoate (187.1 mg, 0.6 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was then stirred at rt overnight. The mixture was filtered through filter paper and washed with DCM (3 × 2 mL). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography purification eluting with MeOH / CH2Cl2 gradients (0-10%). The crude product was obtained and further triturated with MeOH (2 mL). The suspension was filtered through filter paper to afford N-{(4S)-4-{[(2S)-2-({4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-3-methylbutanoyl]amino}-5-[4- (hydroxymethyl)anilino]-5-oxopentyl}urea as a white solid (150.0 mg, 48.5% yield).

[0347] LC-MS: mass calcd for C29H42N6O7: 586.69, found: m / z = 588.35 [M+H]+.

[0348] 1H NMR (400 MHz, DMSO-d6) δ 9.36 (d, J = 31.0 Hz, 1H), 8.14 (t, J = 8.1 Hz, 1H), 7.89 (dd, J = 19.0, 8.2 Hz, 1H), 7.61 (dd, J = 8.6, 2.2 Hz, 2H), 7.24 (dd, J = 8.4, 4.5 Hz, 2H), 6.05 – 5.92 (m, 1H), 5.38 (s, 2H), 5.09 (t, J = 5.5 Hz, 1H), 4.43 (d, J = 5.1 Hz, 2H), 4.36 – 4.29 (m, 1H), 4.21 – 4.13 (m, 1H), 4.12 – 4.06 (m, 2H), 4.05 – 4.01 (m, 2H), 3.66 – 3.51 (m, 2H), 3.45 – 3.38 (m, 1H), 3.17 (d, J = 5.1 Hz, 1H), 3.06 – 2.89 (m, 2H), 2.68 – 2.53 (m, 3H), 2.43 – 2.33 (m, 1H), 2.15 – 2.01 (m, 1H), 1.87 – 1.76 (m, 2H), 1.75 – 1.55 (m, 2H), 1.51 – 1.31 (m, 2H), 0.94 – 0.86 (m, 6H) ppm. Example 35: Synthesis of N-[(4S,7S)-18-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-{[4-(hydroxymethyl)anilino]carbonyl}-6,9,18-trioxo-7-(propan-2-yl)-12,15- dioxa-5,8-diazaoctadec-1-yl]urea.tep : ynt esis of -( -{ -[ , - i e y ro- , , , -tetra y ro- , -oxazonin- ( )-yl]-3- oxopropoxy}ethoxy)propanoic acid.

[0349] 7,8-Didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (300.0 mg, 2.4 mmol) was dissolved in DMF (10 mL) in a single-necked flask. DIEA (1.2 g, 9.6 mmol), 3,3'-(ethane- 1,2-diylbis(oxy))dipropionic acid (1.0 g, 4.8 mmol, 2.0 eq), HOBt monohydrate (734.1 mg, 4.8 mmol), and EDCI (918.9 mg, 4.8 mmol) were added, the flask was purged with N2(3–5 cycles), and the mixture was stirred at rt overnight. Reaction completion was confirmed byLC-MS. The mixture was concentrated under reduced pressure and purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min) to afford 3-(2-{3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-3-oxopropoxy}ethoxy)propanoic acid as a pale yellow oil (420.2 mg, 55.9% yield).

[0350] LC-MS: mass calcd for C15H23NO6: 313.15, found: m / z = 314.18 [M+H]+.

[0351] 1H NMR (400 MHz, CD3OD) δ 4.28 (p, J = 2.5 Hz, 2H), 4.15 (q, J = 2.6 Hz, 2H), 3.86 – 3.71 (m, 7H), 3.65 – 3.57 (m, 5H), 2.71 – 2.64 (m, 2H), 2.56 (td, J = 6.3, 1.5 Hz, 2H), 2.07 – 1.92 (m, 2H) ppm. Step 2: Synthesis of 2,5-dioxopyrrolidin-1-yl 3-(2-{3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-3-oxopropoxy}ethoxy)propanoate.

[0352] 3-(2-{3-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- oxopropoxy}ethoxy)propanoic acid (420.2 mg, 1.3 mmol) was dissolved in CH2Cl2 (5 mL) in a single-necked flask. DIEA (346.6 mg, 2.7 mmol) was added, the flask was purged with N2(3 cycles), and the mixture was cooled to 0 °C using an ice bath. DSC (687.0 mg, 2.7 mmol) was added, and the reaction was stirred at rt for 2 h. Reaction completion was confirmed by LC-MS. Solvents were removed under reduced pressure, and the mixture was taken directly to the next step without purification.

[0353] LC-MS: mass calcd for C19H26N2O8: 410.17, found: m / z = 411.15 [M+H]+. Step 3: Synthesis of N-[(4S,7S)-18-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]- 4-{[4-(hydroxymethyl)anilino]carbonyl}-6,9,18-trioxo-7-(propan-2-yl)-12,15-dioxa-5,8- diazaoctadec-1-yl]urea.

[0354] To a mixture of (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4- (hydroxymethyl)phenyl)-5-ureidopentanamide (508.5 mg, 1.3 mmol) and 2,5-dioxopyrrolidin- 1-yl 3-(2-{3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- oxopropoxy}ethoxy)propanoate (550.0 mg, 1.3 mmol), DMF (5 mL) was added. TEA (406.8 mg, 4.0 mmol) was added, and the reaction was stirred at rt overnight. The mixture was concentrated under reduced pressure and purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min) to afford N-[(4S,7S)-18-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-{[4- (hydroxymethyl)anilino]carbonyl}-6,9,18-trioxo-7-(propan-2-yl)-12,15-dioxa-5,8- diazaoctadec-1-yl]urea as a white solid (4500 mg 498% yield over 2 steps)

[0355] LC-MS: mass calcd for C33H50N6O9: 674.36, found: m / z = 675.37 [M+H]+.

[0356] 1H NMR (400 MHz, CD3OD) δ 7.59 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 4.59 – 4.52 (m, 3H), 4.30 – 4.22 (m, 3H), 4.14 (q, J = 2.7 Hz, 2H), 3.83 – 3.66 (m, 7H), 3.63 – 3.55 (m, 5H), 3.23 – 3.07 (m, 2H), 2.68 – 2.52 (m, 4H), 2.18 – 2.07 (m, 1H), 2.04 – 1.87 (m, 3H), 1.82 – 1.71 (m, 1H), 1.67 – 1.51 (m, 2H), 1.00 (t, J = 6.8 Hz, 6H) ppm. Example 36: Synthesis of (3S)-4-{[(2S)-1-({(2S)-5-(carbamoylamino)-1-[4- (hydroxymethyl)anilino]-1-oxopentan-2-yl}amino)-3-methyl-1-oxobutan-2-yl]amino}-3-({4- [7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxaobutanoyl}amino)-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.Step 1: Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-(((S)-1-((4- (hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2- yl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate.

[0357] (S)-2-((S)-2-Amino-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)- 5-ureidopentanamide (310.0 mg, 0.8 mmol) was dissolved in DMF (6 mL) in a single-neck flask. To this solution were added DIEA (317.2 mg, 2.5 mmol), (S)-3-((tert- butoxycarbonyl)amino)-3-carboxypropyl (2-(trimethylammonio)ethyl) phosphate (471.2 mg, 1.2 mmol), HOBt monohydrate (221.2 mg, 1.4 mmol), and EDCI (313.1 mg, 1.6 mmol). The mixture was purged with N₂ (3–5 cycles) and stirred at rt overnight. The crude reaction mixture was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% TFA (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-(((S)-1-((4- (hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2- yl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate as a white solid (339.1 mg, 55.4% yield).

[0358] LC-MS: mass calcd for C32H56N7O11P: 745.38, found: m / z = 746.43 [M+H]+.

[0359] 1H NMR (400 MHz, CD3OD) δ 7.56 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 4.55 (s, 2H), 4.48 (dd, J = 9.3, 4.9 Hz, 1H), 4.33 – 4.23 (m, 3H), 4.20 (d, J = 6.8 Hz, 1H), 4.06 – 3.91 (m, 2H), 3.65 – 3.58 (m, 2H), 3.18 (s, 9H), 3.16 – 3.08 (m, 2H), 2.19 – 2.06 (m, 2H), 1.96 – 1.70 (m, 3H), 1.64 – 1.51 (m, 2H), 1.44 (s, 9H), 0.98 (dd, J = 6.8, 3.1 Hz, 6H) ppm.

[0360] 31P NMR (162 MHz, CD3OD) δ -0.49 (s, 1P) ppm. Step 2: Synthesis of (S)-3-amino-4-(((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5- ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutyl (2- (trimethylammonio)ethyl) phosphate trifluoroacetate.

[0361] (S)-3-((tert-Butoxycarbonyl)amino)-4-(((S)-1-(((S)-1-((4- (hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2- yl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate (339.3 mg, 0.5 mmol) was dissolved in CH2Cl2 (5 mL) in a single-neck flask. TFA (1 mL) was added, and the reaction mixture was stirred at rt for 1 h. Reaction completion was confirmed by LC-MS. The mixture was concentrated and lyophilized to afford (S)-3-amino-4-(((S)-1-(((S)-1-((4- (hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate as a pale- yellow solid (400.2 mg, 119.8% yield).

[0362] LC-MS: mass calcd for C27H48N7O9P: 645.33, found: m / z = 646.38 [M+H]+. Step 3: Synthesis of (3S)-4-{[(2S)-1-({(2S)-5-(carbamoylamino)-1-[4- (hydroxymethyl)anilino]-1-oxopentan-2-yl}amino)-3-methyl-1-oxobutan-2-yl]amino}-3-({4- [7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.

[0363] (S)-3-Amino-4-(((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo- 5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutyl (2- (trimethylammonio)ethyl) phosphate trifluoroacetate (130.0 mg, 0.2 mmol) was dissolved in DMF (3 mL) in a single-neck flask. TEA (81.3 mg, 0.8 mmol) was added, and the mixture was purged with N₂ (3–5 cycles). The solution was cooled in an ice bath to 0 °C, and 2,5- dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoate (71.3 mg, 0.2 mmol) was added. The mixture was stirred at rt for 2 h. The crude reaction mixture was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford (3S)-4-{[(2S)-1-({(2S)-5- (carbamoylamino)-1-[4-(hydroxymethyl)anilino]-1-oxopentan-2-yl}amino)-3-methyl-1- oxobutan-2-yl]amino}-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate as a white solid (53.2 mg, 31.1% yield).

[0364] LC-MS: mass calcd for C38H61N8O12P: 852.41, found: m / z = 853.46 [M+H]+.

[0365] 1H NMR (400 MHz, CD3OD) δ 7.59 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.55 (s, 2H), 4.51 – 4.46 (m, 1H), 4.45 – 4.36 (m, 1H), 4.28 – 4.15 (m, 4H), 4.12 (s, 2H), 4.09 – 3.90 (m, 3H), 3.83 – 3.73 (m, 2H), 3.68 (t, J = 5.8 Hz, 2H), 3.57 – 3.50 (m, 2H), 3.18 (s, 1H), 3.15 (s, 9H), 3.13 – 3.08 (m, 1H), 2.79 – 2.70 (m, 2H), 2.62 – 2.46 (m, 2H), 2.27 – 2.16 (m, 2H), 2.09 – 1.86 (m, 4H), 1.84 – 1.69 (m, 1H), 1.64 – 1.48 (m, 2H), 1.04 – 0.94 (m, 6H) ppm.

[0366] 31P NMR (162 MHz, CD3OD) δ -0.39 (s, 1P) ppm.Example 37: Synthesis of N-[(4S)-4-{[(2S)-2-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-3-methylbutanoyl]amino}-5-{4-[({[(2,5- dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]anilino}-5-oxopentyl]urea.nin- 5(2H)-yl]-4-oxobutanoyl}amino)-3-methylbutanoyl]amino}-5-{4-[({[(2,5-dioxopyrrolidin-1- yl)oxy]carbonyl}oxy)methyl]anilino}-5-oxopentyl]urea.

[0367] N-{(4S)-4-{[(2S)-2-({4-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-oxobutanoyl}amino)-3-methylbutanoyl]amino}-5-[4-(hydroxymethyl)anilino]-5- oxopentyl}urea (120.1 mg, 0.2 mmol) was dissolved in DMF (3 mL) in a single-neck flask. TEA (62.3 mg, 0.6 mmol) was added, and the solution was purged with N₂ (3–5 cycles). The reaction mixture was cooled in an ice bath to 0 °C, and DSC (115.0 mg, 0.4 mmol) was added slowly. The mixture was stirred at rt for 6 h. Reaction progress was monitored by LC-MS. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography purification eluting with EA / PE gradients (0-100%) to afford the N- [(4S)-4-{[(2S)-2-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-3-methylbutanoyl]amino}-5-{4-[({[(2,5-dioxopyrrolidin-1- yl)oxy]carbonyl}oxy)methyl]anilino}-5-oxopentyl]urea as a yellow solid (110.2 mg, 73.9% yield).

[0368] LC-MS: mass calcd for C34H45N7O11: 727.32, found: m / z = 728.33 [M+H]+.Example 38: Synthesis of N-[(4S,7S)-18-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-({4-[({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]anilino}carbonyl)- 6,9,18-trioxo-7-(propan-2,15-dioxa-5,8-diazaoctadec-1-yl]urea.-yl]- 4-({4-[({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]anilino}carbonyl)-6,9,18- trioxo-7-(propan-2-yl)-12,15-dioxa-5,8-diazaoctadec-1-yl]urea.

[0369] N-[(4S,7S)-18-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]- 4-{[4-(hydroxymethyl)anilino]carbonyl}-6,9,18-trioxo-7-(propan-2-yl)-12,15-dioxa-5,8- diazaoctadec-1-yl]urea (300.0 mg, 0.4 mmol) was dissolved in DMF (5 mL) in a single-necked flask. TEA (135.0 mg, 1.3 mmol) was added, the flask was purged with N2 (3 cycles), and the mixture was cooled to 0 °C using an ice bath. DSC (227.8 mg, 0.9 mmol) was added slowly. The reaction was stirred at rt for 6 h, and solvents were removed under reduced pressure to give crude N-[(4S,7S)-18-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-({4- [({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]anilino}carbonyl)-6,9,18-trioxo-7- (propan-2-yl)-12,15-dioxa-5,8-diazaoctadec-1-yl]urea as a colorless oil (360.8 mg, 99.5% yield).

[0370] LC-MS: mass calcd for C38H53N7O13: 815.37, found: m / z = 816.35 [M+H]+. Example 39: Synthesis of (3S)-4-{[(2S)-1-{[(2S)-5-(carbamoylamino)-1-{4-[({[(2,5- dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]anilino}-1-oxopentan-2-yl]amino}-3-methyl-S (2,5- dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]anilino}-1-oxopentan-2-yl]amino}-3-methyl- 1-oxobutan-2-yl]amino}-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.

[0371] (3S)-4-{[(2S)-1-({(2S)-5-(Carbamoylamino)-1-[4- (hydroxymethyl)anilino]-1-oxopentan-2-yl}amino)-3-methyl-1-oxobutan-2-yl]amino}-3-({4- [7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate (50.0 mg, 0.06 mmol) was dissolved in DMF (2 mL) in a single-neck flask. TEA (18.2 mg, 0.18 mmol) was added, and the solution was purged with N₂ (3–5 cycles). The mixture was cooled in an ice bath to 0 °C, and DSC (33.3 mg, 0.13 mmol) was added. The mixture was stirred at rt for 6 h. Reaction progress was monitored by LC-MS. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography purification eluting with EA / PE gradients (0-100%) to afford the (3S)-4-{[(2S)-1-{[(2S)-5-(carbamoylamino)-1-{4-[({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]anilino}-1-oxopentan-2-yl]amino}-3-methyl-1-oxobutan-2- yl]amino}-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate as a yellow solid (36 mg, 61.8% yield).

[0372] LC-MS: mass calcd for C43H64N9O16P: 993.42, found: m / z = 994.54 [M+H]+Example 40: Synthesis of ({3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl}amino)acetic acidStep 1: Synthesis of tert-butyl ({3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl}amino)acetate.

[0373] 3-[7,8-Didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoic acid (200.0 mg, 0.9 mmol) was dissolved in DMF (10 mL), then tert- butyl glycinate (144.2 mg, 1.1 mmol), HOBt monohydrate (248.1 mg, 1.8 mmol), DIEA (356.6 mg, 2.8 mmol), EDCI (352.5 mg, 1.8 mmol) were added. The mixture was stirred at rt overnight, while being monitored by LC-MS. Once the reaction was completed, the mixture was diluted with EA (50 mL), then washed with water (3 x 20 mL), LiCl (aq., 5 wt%) (3 x 20 mL), NaCl (aq., sat.) (3 x 20 mL). The collected organic layer was dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude mixture was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractionswere combined and lyophilized to afford the tert-butyl ({3-[7,8-didehydro-3,4,6,9-tetrahydro- 1,5-oxazonin-5(2H)-ylsulfonyl]propanoyl}amino)acetate as a white solid (200.3 mg, 70.0% yield).

[0374] 1H NMR (400 MHz, CD3OD) δ 4.14 (t, J = 2.4 Hz, 2H), 4.02 (t, J = 2.4 Hz, 2H), 3.91 – 3.82 (m, 4H), 3.53 – 3.47 (m, 2H), 3.42 – 3.34 (m, 2H), 2.75 (t, J = 7.4 Hz, 2H), 1.91 – 1.83 (m, 2H), 1.47 (s, 9H) ppm. Step 2: Synthesis of ({3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl}amino)acetic acid.

[0375] tert-Butyl ({3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl}amino)acetate (200.3 mg, 0.5 mmol) was dissolved in CH2Cl2(8 mL), then TFA (2 mL) was dropwise added at 0 °C (ice / water bath). The mixture was stirred at 0 °C for 1 h, while being monitored by LC-MS. Once the reaction was completed, the crude mixture was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford the ({3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]propanoyl}amino)acetic acid as a white solid (73.1 mg, 43.0% yield).

[0376] LC-MS: mass calcd for C12H18N2O6S: 318.09, found: m / z = 319.13 [M+H]+.

[0377] 1H NMR (400 MHz, CD3OD) δ 4.16 – 4.10 (m, 2H), 4.05 – 3.99 (m, 2H), 3.93 (s, 2H), 3.90 – 3.85 (m, 2H), 3.58 – 3.47 (m, 2H), 3.39 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.92 – 1.82 (m, 2H) ppm. Example 41: Synthesis of (3S)-3-carboxy-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)propyl 2-(trimethylazaniumyl)ethyl phosphate.Scheme:sphate trifluoroacetate.

[0378] (S)-3-((tert-Butoxycarbonyl)amino)-3-carboxypropyl (2- (trimethylammonio)ethyl) phosphate (400.1 mg, 1.0 mmol) was dissolved in CH2Cl2(4 mL) in a single-neck flask. TFA (1.0 mL) was added, and the reaction mixture was stirred at rt for 2 h. Reaction progress was monitored by LC-MS until complete consumption of the starting material. The mixture was concentrated under reduced pressure to afford crude (S)-3-amino- 3-carboxypropyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate as a pale-yellow oil (320.2 mg, 83.9% yield).

[0379] LC-MS: mass calcd for C9H21N2O6P: 284.11, found: m / z = 285.00 [M+H]+. Step 2: Synthesis of (3S)-3-carboxy-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-oxobutanoyl}amino)propyl 2-(trimethylazaniumyl)ethyl phosphate.

[0380] (S)-3-Amino-3-carboxypropyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate (200.0 mg, 0.7 mmol) was dissolved in DMF (3 mL) in a single-neck flask. TEA (213.3 mg, 2.1 mmol) and 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro- 1,5-oxazonin-5(2H)-yl]-4-oxobutanoate (249.2 mg, 0.8 mmol) were added at 0 °C (ice bath). The mixture was purged with N2(3–5 cycles) and stirred at rt overnight. The crude reaction mixture was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford (3S)-3-carboxy-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)propyl 2-(trimethylazaniumyl)ethyl phosphate as a yellow solid (51.0 mg, 14.1% yield).

[0381] LC-MS: mass calcd for C20H34N2O9P: 491.20, found: m / z = 492.25 [M+H]+.

[0382] 1H NMR (400 MHz, CD3OD) δ 4.45 – 4.39 (m, 1H), 4.32 – 4.19 (m, 4H), 4.11 (s, 2H), 4.06 – 3.89 (m, 2H), 3.82 – 3.78 (m, 1H), 3.77 – 3.73 (m, 1H), 3.68 (t, J = 5.7 Hz, 1H), 3.65 – 3.60 (m, 2H), 3.59 – 3.54 (m, 1H), 3.21 (s, 9H), 2.70 – 2.63 (m, 2H), 2.61 – 2.49 (m, 2H), 2.22 – 2.11 (m, 1H), 2.03 – 1.95 (m, 2H), 1.92 – 1.84 (m, 1H) ppm. Example 42: Synthesis of (3S)-3-carboxy-3-({3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-ylsulfonyl]propanoyl}amino)propyl 2-(trimethylazaniumyl)ethyl phosphate.St y y , y , , , y , onin- 5(2H)-ylsulfonyl]propanoyl}amino)propyl 2-(trimethylazaniumyl)ethyl phosphate.

[0383] (S)-3-Amino-3-carboxypropyl (2-(trimethylammonio)ethyl) phosphate (150.0 mg, 0.5 mmol) was dissolved in DMF (3 mL) in a single-neck flask. TEA (151.8 mg, 1.5 mmol) and 2,5-dioxopyrrolidin-1-yl 3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-ylsulfonyl]propanoate (197.1 mg, 0.6 mmol) were added. The mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, then purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% in 30 min). Desired fraction was collection and lyophilized to afford (3S)-3-carboxy- 3-({3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-ylsulfonyl]propanoyl}amino)propyl 2-(trimethylazaniumyl)ethyl phosphate as a yellow solid (44.2 mg, 15.9% yield).

[0384] LC-MS: mass calcd for C19H34N3O10PS: 527.17, found: m / z = 528.19 [M+H]+.

[0385] 1H NMR (400 MHz, D2O) δ 4.54 (dd, J = 8.7, 4.9 Hz, 1H), 4.36 – 4.28 (m, 2H), 4.23 (t, J = 2.3 Hz, 2H), 4.09 (t, J = 2.5 Hz, 2H), 4.07 – 3.97 (m, 2H), 3.97 – 3.94 (m, 2H), 3.70 – 3.66 (m, 2H), 3.59 – 3.52 (m, 4H), 3.24 (s, 9H), 2.86 (t, J = 7.0 Hz, 2H), 2.32 – 2.22 (m, 1H), 2.15 – 2.04 (m, 1H), 1.96 – 1.88 (m, 2H) ppm. 31P NMR (162 MHz, D2O) δ -0.38 (s, 1P) ppm. Example 43: Synthesis of (3S)-3-[(3-carboxypropanoyl)amino]-4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate. SchemeStep: Synthesis of (3S)-3-[(3-carboxypropanoyl)amino]-4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.

[0386] A solution of (3S)-3-amino-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate hydrochloride (30.5 mg, 76.1 µmol) in CH2Cl2(1 mL) and DMSO (0.5 mL) was placed in a RBF. To this solution were added TEA (23.1 mg, 0.2 mmol) and dihydrofuran-2,5-dione (8.4 mg, 84.3 µmol). The reaction mixture was stirred at rt for 1 h. Reaction progress was monitored by LC-MS. Themixture was concentrated under reduced pressure, and the crude residue was purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (0–30% ACN in 30 min). The purified fractions were lyophilized to afford (3S)-3-[(3- carboxypropanoyl)amino]-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutyl 2-(trimethylazaniumyl)ethyl phosphate as a colorless oil (5.0 mg, 14.3% yield).

[0387] LC-MS: mass calcd for C20H34N3O9P: 491.20, found: m / z = 492.31 [M+H]+.

[0388] 1H NMR (400 MHz, CD3OD) δ 5.00 – 4.96 (m, 1H), 4.39 – 4.24 (m, 3H), 4.23 – 4.11 (m, 3H), 3.99 – 3.89 (m, 2H), 3.87 – 3.77 (m, 2H), 3.68 – 3.62 (m, 2H), 3.25 (s, 9H), 2.69 – 2.44 (m, 5H), 2.23 – 1.81 (m, 5H) ppm.

[0389] 31P NMR (162 MHz, CD3OD) δ -0.49 ppm. Example 44: Synthesis of 5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- ylsulfonyl]-N,N-dimethylnaphthalen-1-amine. Scheme:Step 1: Synthesis of 5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-ylsulfonyl]-N,N- dimethylnaphthalen-1-amine.

[0390] To a solution of 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (300.0 mg, 2.4 mmol) in CH2Cl2(8 mL), 5-(dimethylamino)naphthalene-1-sulfonyl chloride (646.5 mg, 2.4 mmol) and TEA (485.7 mg, 4.8 mmol) were added. The mixture was stirred at rt for 1 h. Upon completion of the reaction, the mixture was concentrated by rotary evaporation under reduced pressure, and the residue was triturated with MeOH (3 mL) for 1 h. The resulting suspension was filtered, the solid was washed with cold MeOH (1 mL), and the filter cake wasdried under reduced pressure to afford 5-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-ylsulfonyl]-N,N-dimethylnaphthalen-1-amineas a yellow solid (599.2 mg, 70.1% yield).

[0391] 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 8.5 Hz, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.19 (dd, J = 7.3, 1.2 Hz, 1H), 7.59 – 7.50 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 4.09 – 3.99 (m, 4H), 3.80 – 3.71 (m, 2H), 3.52 – 3.42 (m, 2H), 2.89 (s, 6H), 1.79 (t, J = 5.5 Hz, 2H) ppm. Example 45: Synthesis of N-{3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- oxopropyl}-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide. SchemeStep 1: Synthesis of N-{3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- oxopropyl}-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide.

[0392] In a 100 mL RBF, 3-amino-1-[7,8-didehydro-3,4,6,9-tetrahydro-1,5- oxazonin-5(2H)-yl]propan-1-one (129.0 mg, 0.7 mmol), 2,5-dioxopyrrolidin-1-yl 3-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate (175.0 mg, 0.7 mmol) were dissolved THF (15 mL), and then TEA (1.5 mL, 1.1 g, 10.8 mmol) was added. The mixture was allowed to stir at rt overnight while being monitored with TLC. The crude was concentrated by rotary evaporation under reduced pressure, and purified with silica gel column chromatography purification eluting with MeOH / CH2Cl2 gradients (0-5%) to afford N-{3-[7,8-didehydro- 3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3-oxopropyl}-3-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)propenamide as a white solid (120.7 mg, 52.6% yield).

[0393] MS: mass calcd for C17H21N3O5: 347.12, found: m / z = 348.10 [M+H]+

[0394] 1H NMR (600 MHz, CDCl3) δ 6.66 (s, 2H), 6.52 (br s, 1H), 4.25 – 4.02 (m, 4H), 3.80 – 3.72 (m, 4H), 3.59 – 3.54 (m, 2H), 3.50 – 3.45 (m, 2H), 2.53 – 2.46 (m, 2H), 2.45 – 2.40 (m, 2H), 1.96 – 1.90 (m, 2H) ppm.Example 46: Synthesis of (3S)-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-oxobutanoyl}amino)-4-oxo-4-{[(3R,5S)-tricyclo[3.3.1.13,7]decan-1- ylmethyl]amino}butyl 2-(trimethylazaniumyl)ethyl phosphate.Step 1: Synthesis of (S)-4-((((3S,5S,7S)-adamantan-1-yl)methyl)amino)-3-((tert- butoxycarbonyl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate.

[0395] (S)-3-((tert-Butoxycarbonyl)amino)-3-carboxypropyl (2- (trimethylammonio)ethyl) phosphate (4.5 g, 11.7 mmol) and ((3r,5r,7r)-adamantan-1- yl)methanamine (1.9 g, 11.7 mmol) were dissolved in DMF (100 mL) in a single-neck flask. To this solution were added DIEA (6.0 g, 46.8 mmol), HOBt monohydrate (3.2 g, 20.9 mmol), and EDCI (4.5 g, 23.4 mmol). The mixture was purged with N2and stirred at rt overnight.Reaction progress was monitored by LC-MS until complete consumption of starting materials. The solvent was removed under reduced pressure, and the residue was purified by preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford (S)-4- ((((3S,5S,7S)-adamantan-1-yl)methyl)amino)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl (2- (trimethylammonio)ethyl) phosphate as a pale-yellow solid (3.5 g, 56.5% yield).

[0396] LC-MS: mass calcd for C25H46N3O7P: 531.31, found: m / z = 532.42 [M+H]+.

[0397] 1H NMR (400 MHz, CD3OD) δ 4.35 – 4.27 (m, 2H), 4.22 – 4.18 (m, 1H), 4.04 – 3.93 (m, 2H), 3.69 – 3.62 (m, 2H), 3.25 (s, 9H), 2.99 (dd, J = 13.4, 6.7 Hz, 1H), 2.88 – 2.81 (m, 1H), 2.13 – 2.06 (m, 1H), 1.97 (s, 3H), 1.93 – 1.86 (m, 1H), 1.79 – 1.65 (m, 8H), 1.55 (s, 6H), 1.47 (s, 9H) ppm. Step 2: Synthesis of (S)-4-((((3S,5S,7S)-adamantan-1-yl)methyl)amino)-3-amino-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate.

[0398] (S)-4-((((3S,5S,7S)-Adamantan-1-yl)methyl)amino)-3-((tert- butoxycarbonyl)amino)-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate (3.5 g, 6.6 mmol) was dissolved in CH2Cl2(8 mL) in a single-neck flask. TFA (3 mL) was added at 0 °C (ice bath), and the reaction mixture was stirred at rt for 1 h. Reaction progress was monitored by LC-MS until complete consumption of the starting material. The mixture was concentrated under reduced pressure and the residue was dissolved in H2O (5mL) and ACN (5 mL) and lyophilized to afford (S)-4-((((3S,5S,7S)-adamantan-1-yl)methyl)amino)-3-amino-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate as a pale-yellow oil (4.6 g, 127.8% yield).

[0399] LC-MS: mass calcd for C31H51N4O8P: 431.25, found: m / z = 432.37 [M+H]+.

[0400] 1H NMR (400 MHz, CD3OD) δ 4.41 – 4.28 (m, 2H), 4.13 – 4.00 (m, 3H), 3.73 – 3.63 (m, 2H), 3.26 (s, 9H), 3.07 – 2.97 (m, 1H), 2.93 – 2.85 (m, 1H), 2.29 – 2.15 (m, 1H), 2.14 – 2.05 (m, 1H), 1.99 (s, 3H), 1.81 – 1.75 (m, 3H), 1.72 – 1.67 (m, 3H), 1.59 – 1.53 (m, 7H) ppm. Step 3: Synthesis of (3S)-3-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-4-oxo-4-{[(3R,5S)-tricyclo[3.3.1.13,7]decan-1-ylmethyl]amino}butyl 2- (trimethylazaniumyl)ethyl phosphate.

[0401] (S)-4-((((3S,5S,7S)-Adamantan-1-yl)methyl)amino)-3-amino-4-oxobutyl (2-(trimethylammonio)ethyl) phosphate trifluoroacetate (4.6 g, 8.4 mmol) was dissolved in DMF (5 mL) in a single-neck flask and purged with N2(3 cycles). TEA (3.2 g, 31.9 mmol) and 2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoate (3.4 g, 10.7 mmol) were dissolved in DMF (3 mL) and added at 0 °C (ice bath). The mixture was stirred at rt for 2 h. Reaction progress was monitored by LC-MS until complete consumption of starting materials. The mixture was concentrated under reduced pressure, and the residue was purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product- containing fractions were combined and lyophilized to afford (3S)-3-({4-[7,8-didehydro- 3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-4-oxo-4-{[(3R,5S)- tricyclo[3.3.1.13,7]decan-1-ylmethyl]amino}butyl 2-(trimethylazaniumyl)ethyl phosphate as a pale-yellow solid (1.6 g, 29.8% yield).

[0402] LC-MS: mass calcd for C31H51N4O8P: 638.34, found: m / z = 639.37 [M+H]+.

[0403] 1H NMR (400 MHz, D2O) δ 7.96 (t, J = 6.5 Hz, 1H), 4.48 – 4.42 (m, 1H), 4.42 – 4.28 (m, 3H), 4.28 – 4.17 (m, 3H), 4.09 – 3.97 (m, 2H), 3.97 – 3.85 (m, 2H), 3.76 – 3.67 (m, 3H), 3.67 – 3.55 (m, 1H), 3.26 (s, 9H), 3.02 – 2.87 (m, 2H), 2.81 (q, J = 6.8 Hz, 2H), 2.73 – 2.57 (m, 2H), 2.33 – 2.20 (m, 1H), 2.15 – 2.03 (m, 2H), 1.98 (s, 4H), 1.78 – 1.62 (m, 6H), 1.49 (s, 6H) ppm.

[0404] 31P NMR (162 MHz, D2O) δ -0.34 (s) ppm. Example 47: Synthesis of (3S)-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- ({[5-(dimethylamino)naphthalen-1-yl]sulfonyl}amino)-4-oxobutyl 2- (trimethylazaniumyl)ethyl phosphate. N O Scheme5- (dimethylamino)naphthalen-1-yl]sulfonyl}amino)-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate.

[0405] (3S)-3-Amino-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate hydrochloride (160.0 mg, 0.4 mmol) was dissolved in CH2Cl2(5 mL) in a single-necked flask, purged with N2three times, and cooled to 0 °C using an ice bath. TEA (124.1 mg, 1.2 mmol) was added dropwise, followed by 5-(dimethylamino)naphthalene-1-sulfonyl chloride (110.3 mg, 0.4 mmol). The mixture was stirred at rt for 1 h, and reaction completion was confirmed by LC-MS. The mixture was concentrated under reduced pressure and purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min). Desired fractions were collected and lyophilized to afford (3S)-4-[7,8-didehydro-3,4,6,9- tetrahydro-1,5-oxazonin-5(2H)-yl]-3-({[5-(dimethylamino)naphthalen-1-yl]sulfonyl}amino)- 4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate as a yellow solid (109.7 mg, 43.0% yield).

[0406] LC-MS: mass calcd for C28H41N4O8PS: 624.24, found: m / z = 625.38 [M+H]+.

[0407] 1H NMR (400 MHz, D2O) δ 8.43 (d, J = 8.6 Hz, 1H), 8.26 – 8.16 (m, 2H), 7.62 (t, J = 8.7, 2H), 7.35 (d, J = 7.6 Hz, 1H), 4.37 – 4.14 (m, 3H), 4.04 – 3.99 (m, 1H), 3.99 – 3.89 (m, 3H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.64 – 3.58 (m, 2H), 3.58 – 3.49 (m, 1H), 3.35 – 3.27 (m, 1H), 3.23 – 3.19 (m, 1H), 3.17 (s, 9H), 3.06 – 2.97 (m, 1H), 2.79 (d, J = 6.3 Hz, 6H), 2.72 – 2.63 (m, 1H), 1.92 – 1.66 (m, 2H), 1.32 – 1.23 (m, 1H), 0.92 – 0.80 (m, 1H) ppm.

[0408] 31P NMR (162 MHz, D2O) δ -0.66 (d, J = 11.5 Hz, 1P) ppm. Example 48: Synthesis of 1,37-di[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]- 4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontane-1,37-dione- 4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontane-1,37-dione.

[0409] 7,8-Didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (103.9 mg, 0.8 mmol) was dissolved in DMF (5 mL) in a single-necked flask. To this solution were added DIEA (171.6 mg, 1.3 mmol), 4,7,10,13,16,19,22,25,28,31,34-undecaoxaheptatriacontanedioic acid (200.0 mg, 0.3 mmol), HOBt monohydrate (127.1 mg, 0.8 mmol), and EDCI (159.2 mg, 0.8 mmol). The mixture was stirred at rt for 16 h, and reaction completion was confirmed by MS. The mixture was concentrated under reduced pressure and purified using preparative RP-LC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5-95% ACN / water in 30 min). Desired fractions were collected and freeze-dried to afford 1,37-di[7,8-didehydro- 3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4,7,10,13,16,19,22,25,28,31,34- undecaoxaheptatriacontane-1,37-dione as a yellow oil (115.5 mg, 42.6% yield).

[0410] LC-MS: mass calcd for C40H68N2O15: 816.46, found: m / z = 817.39 [M+H]+.

[0411] 1H NMR (400 MHz, CDCl3) δ 4.28 (s, 2H), 4.12 (s, 5H), 3.83 – 3.75 (m, 8H), 3.65 – 3.60 (m, 44H), 2.63 (t, J = 6.7 Hz, 4H), 2.03 – 1.91 (m, 4H) ppm. Example 49: Synthesis of (3S)-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- {[({5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)- 3,3-dimethyl-1-[(4-methylphenyl)sulfonyl]pentan-2-yl}oxy)carbonyl]amino}-4-oxobutyl 2- (trimethylazaniumyl)ethyl phosphate.tep : yntess of -amno-,- mety--tosypentan--o.

[0412] 5-Azido-3,3-dimethyl-1-tosylpentan-2-ol was dissolved in CH3OH (10 mL) in a single-neck flask. Pd / C (10 wt% dry, 50.0 mg) was added, and the mixture was purged with H2. The reaction mixture was stirred at rt for 45 min under 1 atm H2 atmosphere. The reaction progress was monitored by TLC. The mixture was filtered through Celite and concentrated under reduced pressure. The resulting crude was purified using preparative RP- HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95%ACN in 30 min). Product-containing fractions were combined and lyophilized to afford 5- amino-3,3-dimethyl-1-tosylpentan-2-ol as a white solid (540.0 mg, 70.0% yield).

[0413] LC-MS: mass calcd for C14H23NO3S: 285.14, found: m / z = 286.18 [M+H]+.

[0414] 1H NMR (400 MHz, CD3OD) δ 7.85 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 3.80 (dd, J = 9.2, 1.4 Hz, 1H), 3.40 (dd, J = 14.6, 1.4 Hz, 1H), 3.27 (dd, J = 14.6, 9.3 Hz, 1H), 3.05 – 2.89 (m, 2H), 2.48 (s, 3H), 1.70 (ddd, J = 13.2, 11.6, 5.7 Hz, 1H), 1.51 (ddd, J = 13.3, 11.6, 5.2 Hz, 1H), 0.89 (d, J = 12.7 Hz, 6H) ppm. Step 2: Synthesis of 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-{4- hydroxy-3,3-dimethyl-5-[(4-methylphenyl)sulfonyl]pentyl}-4-oxobutanamide.

[0415] 5-Amino-3,3-dimethyl-1-tosylpentan-2-ol (700.1 mg, 2.5 mmol) was dissolved in CH2Cl2 (7 mL) in a single-neck flask.2,5-dioxopyrrolidin-1-yl 4-[7,8-didehydro- 3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoate (870.2 mg, 2.7 mmol), TEA (496.0 mg, 4.9 mmol) were added, and the mixture was stirred at rt for 1 h. The mixture was diluted with water (3 x 10 mL) and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The resulting crude mixture was purified with silica gel column chromatography purification eluting with MeOH / CH2Cl2gradients (0-10%) to afford the 4- [7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-N-{4-hydroxy-3,3-dimethyl-5-[(4- methylphenyl)sulfonyl]pentyl}-4-oxobutanamide as a colorless oil (390.3 mg, 33.0% yield).

[0416] LC-MS: mass calcd for C25H36N2O6S: 492.23, found: m / z = 493.22 [M+H]+.

[0417] 1H NMR (400 MHz,CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 4.34 – 4.20 (m, 2H), 4.15 (d, J = 2.5 Hz, 2H), 3.91 (d, J = 9.2 Hz, 1H), 3.81 (dt, J = 23.1, 5.3 Hz, 2H), 3.68 (d, J = 5.8 Hz, 1H), 3.65 – 3.59 (m, 1H), 3.30 – 3.14 (m, 4H), 2.74 (s, 3H), 2.71 (d, J = 6.4 Hz, 2H), 2.55 (dt, J = 12.3, 6.3 Hz, 2H), 2.06 – 1.94 (m, 2H), 1.69 – 1.58 (m, 1H), 1.44 – 1.34 (m, 1H), 0.86 (s, 6H) ppm. Step 3: Synthesis of 5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-3,3-dimethyl-1-[(4-methylphenyl)sulfonyl]pentan-2-yl 2,5- dioxopyrrolidin-1-yl carbonate.

[0418] A 100 mL RBF with 4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-N-{4-hydroxy-3,3-dimethyl-5-[(4-methylphenyl)sulfonyl]pentyl}-4-oxobutanamide (130.2 mg, 0.3 mmol) was purged with N2 / vacuum cycle 3 times, before the addition of triphosgene (196.0 mg, 0.7 mmol) and THF (5 mL). The mixture was stirred at 0 °C for 5 min, then pyridine (63.0 mg, 0.8 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 0 °C for 10 min, then slowly warmed to rt for 0.5 h. The mixture was filtered and washed with THF (3 x 3 mL). The resulting filtrate was concentrated by rotary evaporation under reduced pressure. N-Hydroxysuccinimide (91.1 mg, 0.8 mmol) was added, and the flask was purged with N2 / vacuum cycle 3 times, before the addition of THF (10 mL) at 0 °C. Then pyridine (63.0 mg, 0.8 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at 0 °C for 10 min, then slowly warmed to room temperature for 2 h. The mixture was filtered and washed with THF (3 x 3 mL). The resulting filtrate was concentrated by rotary evaporation under reduced pressure. The crude mixture was purified using preparative RP- HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions were combined and lyophilized to afford 5-({4- [7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)-3,3- dimethyl-1-[(4-methylphenyl)sulfonyl]pentan-2-yl 2,5-dioxopyrrolidin-1-yl carbonate as a white solid (34.0 mg, 20.3% yield).

[0419] LC-MS: mass calcd for C30H39N3O10S: 633.24, found: m / z = 634.26 [M+H]+. Step 4: Synthesis of (3S)-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- {[({5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4-oxobutanoyl}amino)- 3,3-dimethyl-1-[(4-methylphenyl)sulfonyl]pentan-2-yl}oxy)carbonyl]amino}-4-oxobutyl 2- (trimethylazaniumyl)ethyl phosphate.

[0420] (3S)-3-Amino-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)- yl]-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate hydrochloride (104.0 mg, 243.1 µmol) was dissolved in DMF (3 mL) in a single-neck flask, and TEA (49.2 mg, 486.1 µmol) was added. After stirring at rt for 10 min, 5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-4-oxobutanoyl}amino)-3,3-dimethyl-1-[(4-methylphenyl)sulfonyl]pentan-2-yl 2,5- dioxopyrrolidin-1-yl carbonate (102.7 mg, 162.1 µmol) was added. The reaction was stirred at rt for 1 h. The mixture was concentrated by rotary evaporation under reduced pressure and the residue purified using preparative RP-HPLC employing ACN / water mobile phases acidified with 0.1 vol-% formic acid (5–95% ACN in 30 min). Product-containing fractions werecombined and lyophilized to afford (3S)-4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin- 5(2H)-yl]-3-{[({5-({4-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-4- oxobutanoyl}amino)-3,3-dimethyl-1-[(4-methylphenyl)sulfonyl]pentan-2- yl}oxy)carbonyl]amino}-4-oxobutyl 2-(trimethylazaniumyl)ethyl phosphate as a pale yellow solid (82.0 mg, 55.6% yield).

[0421] LC-MS: mass calcd for C42H64N5O13PS: 909.40, found: m / z = 910.34 [M+H]+. Example 50: Synthesis of N-{3-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-3- oxopropyl}-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide.1-one:

[0422] In a 100 mL RBF, 7,8-didehydro-2,3,4,5,6,9-hexahydro-1,5-oxazonine (168.0 mg, 1.3 mmol) was dissolved in 10 mL of DCM, then 2,5-dioxopyrrolidin-1-yl 2- iodoacetate (760.0 mg, 2.6 mmol), DIEA (0.5 mL, 2.9 mmol) were added. The mixture was stirred at rt for 6 h, while being monitored by TLC. Once the reaction was completed, the mixture was concentrated by rotary evaporation under reduced pressure, the residue was subjected to silica gel column chromatography purification eluting with EA / Hex gradients (60- 100%) to afford 1-[7,8-didehydro-3,4,6,9-tetrahydro-1,5-oxazonin-5(2H)-yl]-2-iodoethan-1- one as a white solid (239.2 mg, 60.8% yield).

[0423] 1H NMR (600 MHz, CDCl3) δ 4.64 (d, J = 17.2 Hz, 2H), 4.32 – 4.16 (m, 2H), 4.07 (dt, J = 4.1, 2.4 Hz, 2H), 3.79 – 3.72 (m, 2H), 3.71 – 3.52 (m, 2H), 1.97 – 1.86 (m, 2H) ppm.

Claims

1. WHAT IS CLAIMED IS:

1. A compound having the following structure: wherein X1, X2, X3, X4, X5, and X6are each independently H, alkyl, aryl, or halogen; or X3and X4or X5and X4together form a saturated or unsaturated 3- to 9- membered carbocyclic ring or heterocyclic ring having one or more heteroatoms selected from N, O, or S, wherein the carbocyclic ring and heterocyclic ring is substituted by halogen; Y is L1-L2-L3-Z; L1is absent or selected from the group consisting of , or ; R2 is H or alkyl; R’ is H alkyl –(CH2)b–phosphorylcholine; (C2)bCOO2, (CH2)bOH,or (CH2)bC(O)NH2, wherein b is 1, 2, or 3; z is 1, 2, 3, or 4; m is an integer between 1 and 15; n is 0, 1, 2, or 3; and is aryl or heteroaryl; L2 is absent or selected from the group consisting , L3is absent or selected from the group consisting of , ; ne, optionally substituted C2-C4 heteroalkylene, arylene, heteroarylene, or C5 or C6 cycloalkylene; R3 is H or alkyl; R5is H, alkyl ; R4 is alkyl, o stituted aryl, or heteroaryl; Z is selected from the group consisting of H, OH, haloge ; consisting of N- hydroxysuccinimide (NHS), sulfo-NHS, pentafluorophenyl (PFP), 4- nitrophenyl (PNP), hydroxybenzotriazole (HOBt), HOAt, and imidazolide esters; X is halogen; and a is 0 or 1.

2. The compound of Claim 1, wherein X1, X2, X3, and X5are each H.

3. The compound of Claim 1, wherein Y is L L L Z L L Z L L Z L L Z 4. The compound of Claim 1, wherein L1is selected from the group consisting of O R' , red 6. The compound of Claim 4, wherein R2 is H or C1-3 alkyl.

7. The compound of Claim 1, wherein L3is selected from the group consisting of , , , sting of 9. The compound of Claim 1, wherein the compound is selected from the group-110-, , , ,